ANNUAL REPORT 2019 EDITORIAL STAFF: Kjetil Taskén Leonardo A

Oslo University Hospital INSTITUTE The Norwegian Radium Hospital Institute for Cancer Research FORINSTITUTE CANCER

Ullernchausseen 70 RESEARCH N–0379 Oslo FOR CANCER Norway P.O. BOX 4953 Nydalen RESEARCH N–0424 Oslo Norway ANNUAL http://ous-research.no/institute/ REPORT 2017

INSTITUTE FOR CANCER RESEARCH ANNUAL REPORT 2017 ANNUAL REPORT 2019 EDITORIAL STAFF: Kjetil Taskén Leonardo A. Meza-Zepeda Peter Wiedswang Kari Aalrust Berger

DESIGN: Espen Liland

PHOTOGRAPHY: Øystein Horgmo, UiO Amalie Huth Hovland, UiO Terje Heiestad Katrine Lunke, Apeland

The photographic theme of this year’s Annual Report is Humans at ICR. - The most important part of ICR is by far its human resources and our collective competence.

FRONT PAGE: Optics inside a flow cytometer. Flow cytometry is used in our research in cancer immunology, immune-oncology and immune monitoring as well as in cell cycle and cell signalling analyses. Advanced technology and competence provided by the Department of Core Facilities is a pillar for cutting-edge research at the Institute for Cancer Research. Advanced infrastructure is financed by OUH, UoO, RCN, Radiumhospitalets Legater, and Norsk Hydros Fond.

PAPER: 150/300 Profimatt CIRCULATION: 800 Contents

4 Taking our legacy into the future 6 Introduction by the Director 8 Organisation and key figures 14 Oslo University Hospital Comprehensive Cancer Centre 15 Precision Cancer Medicine at OUH Comprehensive Cancer Centre

16 Departments and research groups 18 Cancer Genetics 26 Cancer Immunology 34 Molecular Cell Biology 40 Molecular Oncology 46 Radiation Biology 52 Tumor Biology 58 Core Facilities

62 Research centres 64 Centre of Excellence 66 K. G. Jebsen Centres

72 International Collaboration 74 Recent Innovations 76 Publications

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 3 Taking our legacy into the future WHO WE ARE LEGACY IN RESEARCH, INNOVATION AND EDUCATION 1954 The Institute for Cancer Research (ICR) was founded in 1954 representing 65 years of con- tinuous advances in cancer research. Through the years, our work has significantly contributed to better understand cell cycle and cell division, RESEARCH cancer cell biology, cancer genetics, cancer immunology, radiation biology, molecular oncology, tumor biology, and metastasis. In addition, we have contributed to novel methods and implementation of a number of new technologies to help cancer diagnostics and monitoring.

INNOVATION There is also a proud history of translational research and innovation, for example on photomed- icine leading to companies such as Photocure and PCI Biotech and with numerous other past and present translational and innovation projects at the ICR in various stages of development.

EDUCATION Education and dissemination are an integrated part of ICR activities and many masters- and PhD-students and postdocs have received their training at the ICR and have pursued successful careers in research, clinical medicine, administration or in the biotech and pharma sector.

IN NUMBERS Approximately 350 research staff in 25 research groups, 6 core facilities and 1 350 admin unit (organization see pages 8-9) RESEARCH STAFF PAST 5 YEARS (2015-2019)

ICR researchers have raised more than 1.0 billion NOK extramural funding (of total 1.5 billion accounted) 1.00 BILLION NOK 1650 1100 WORKING YEARS PUBLICATIONS Put in 1650 working years (FTEs) Leading to production of more than 1100 (1112) publications (mean IF 6.1, EDUCATED median IF 4.5) 150 PhDs and MScs Educated 66 PhDs and 84 MScs that have graduated (for 2019 Key Figures see pages 10-11).

4 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 - Who we are and what we do WHAT WE DO

VISION: EXCELLENCE IN FIGHTING CANCER

WE AIM TO: • Stay at the cutting edge of cancer research • Educate the leaders of tomorrow in cancer research, cancer diagnostics and treatment • Take a prominent part in developing of new OUH and national strategies for advanced molecular cancer diagnostics, cancer precision medicine and experimental cell therapy (see also page 15)

VALUES: QUALITY, INTEGRITY, TEAMWORK, VISION

■ Objectives Q ■ Ambition U N A IO ■ Global influence L IS ■ Cutting-edge IT V ■ Passion Y

■ Respect

■ Excellence ■ Synergy in research

EXCELLENCE ■ Diversity ■ Trust

■ Generosity

IN FIGHTING ■ Competence

■ Partnerships

■ Solidarity CANCER

■ Openness

M ■ Ethics W Y ■ Responsibility T O ■ I R Loyalty R K ■ Demands EG INT

GOALS 2019-2020 1 Strengthen translational research

2 Strengthen contact, coordination and collaboration with clinicians and diagnostic staff in OUH CCC and beyond

3 Build further excellence in research

4 Establish new SAB

5 Increase internationalisation and technology development

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 5 Introduction by the Director

I am proud to present you with our Annual Report We celebrate our victories at the ICR, and in 2019 we for 2019. The Institute for Cancer Research (ICR) is an have marked the fact that two of the newly awarded institution with approximately 350 employees plus OUH Strategic areas went to the ICR-led projects TEAM- students organised in 25 research groups complemented ACT (led by Ragnhild A. Lothe) and STRATCELL (led by with cutting-edge core facilities. The ICR is a premier Karl-Johan Malmberg). We have celebrated a number institution in basic and translational cancer research of grants from the RCN including several young talent on a national and international arena and has a strong grants and including the start of Digital Life PINpOINT prior track record in translation and innovation. More project, and multiple grants from the Cancer Society, the than one third of the ICR staff is international and come Regional Health Authority for South-Eastern Norway from 37 different countries. and other sources. ICR is also well represented in the new Cancer Society Expert Groups for Lung Cancer In 2019 we worked in the ICR Leadership group, among (headed by Åslaug Helland) and Pancreatic Cancer the Group Leaders and in all ICR departments and (headed by Caroline Verbeke). We have also had the groups to set out and integrate our Vision and Values official opening of the privately funded InvaCell project (Quality-Integrity-Teamwork-Vision, see the previous that formalized a collaboration between the ICR and page). We also set out Goals for 2019-2020, both as the Curie Institute (with Harald Stenmark and Philippe presented under the heading “The ICR into the future!” Chavrier as PIs, donor Trond Paulsen). At Christmas, in the 2018 Annual Report and on the preceding pages we celebrated the award of a highly prestigious ERC in this report. Among our goals for 2019 and 2020 are Consolidator Grant to Johanna Olweus. We have marked to (1) strengthen translational research, (2) to improve the fact that the University of Oslo (UiO)/OUH was contact, coordination and collaboration with clinicians granted a prestigious 6-mEUR Horizon2020 grant, and diagnostic staff in the Oslo University Hospital RESCUER, for precision medicine research on breast Comprehensive Cancer Centre (OUH-CCC) and beyond, cancer (headed by Vessela Kristensen and with strong (3) to build further excellence in research where ICR participation) and that Åslaug Helland received a we would like to see originality, depth, quality, and large KLINBEFORSK grant. The ICR has also received international value. very significant grants for new instrumentation from the Radium Hospital Foundation and from Norsk With respect to goals 1 and 2, I think there are Hydro’s Fund for Cancer Research in 2019. We also numerous outstanding examples of collaborative celebrated internally the award of the OUH Early Career translational and clinical projects throughout this Award to Anita Sveen, the EU Innovation Radar Prize to report. Furthermore, the ICR is a central component Kristian Berg and Theodossis Theodossiou, the award in the new and developing strategies for precision of the Ragnar Mørk’s Prize for Outstanding Research Directormedicine and for cell therapy in the Division for Cancer to Karl-Johan Malmberg and the award of the new ICR Medicine and the OUH-CCC. To build further excellence Prizes Researcher-of-the-year and Employee-of-the- (goal 3), we would like to see a further increase in the year for 2019 to Theodossis Theodossiou and Peter quality of the scientific output. Against this backdrop, Wiedswang, respectively. Furthermore, OUH awarded it is interesting to see that the median impact factor prizes in their bi-annual assessment of best papers of the papers produced is up from 4.1 in 2017 to 5.0 in to ICR researchers Marthe Løvf and Rolf Skotheim 2018 and 4.5 in 2019. Moreover, the fact that the output (May 2019), Muhammad Ali, Zsofia Foldvari, Eirini in terms of the number of papers is increasing, with Giannakopoulou and Johanna Olweus (Nov 2019) and 241 papers in 2019 and more than 40 in the two first Marte Sneeggen and Kay Oliver Schink (Nov 2019). months of 2020 (versus 220 and 186 papers in 2017 and 2018, respectively. This is excellent, particularly In the Department of Cancer Genetics, we welcomed as almost half of the production also has first and/or Tero Aittokallio as a new Group Leader for the senior authors from ICR. ICR innovation activities also Computational Systems Medicine in Cancer Group appear to be progressing well with 10 new DOFIs, 7 new from September 2019 (recruited from Finland) and patent applications filed and 5 patents granted from in Department of Cancer Immunology, Jon Amund ICR inventors. In addition, company collaborations and Kyte has been appointed Group Leader for the interaction appear to be increasing. Immunotherapy Against Solid Cancers Group from 2020. More than 2/3rds of the total ICR funding in 2019 (234.4 of 333.5 MNOK) came from extramural grants which ICR’s strong standing in Norwegian research is also are higher than ever before. ICR scientists have also illustrated by the fact that members of the institute been able to obtain substantial new funding and secured lead a Centre of Excellence (CoE) Centre for Cancer major new grants from the Norwegian Cancer Society, Cell Reprogramming (CanCell, Director Harald the Research Council of Norway, and the South-Eastern Stenmark) and the three K.G. Jebsen centres for Cancer Norway Regional Health Authority as well as private Immunotherapy (Director Johanna Olweus), Colorectal and international sources. Cancer Research (Director Ragnhild A. Lothe), both

6 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Introduction by the Director “Research and innovation with patient benefit in mind”

in the extension phase, and for B Cell Malignancies (Deputy Director June Myklebust), all with strong participation from ICR groups.

The recent advents of the Covid-19 pandemic have had major impacts world-wide and on the Norwegian society at large as well as on OUH and UiO research activity at this time. At the ICR, as part of the hospital and with good support from the leadership at all levels, we decided to keep the institute open throughout the pandemic. - This in recognition of the importance of the science we do and to support the hospital operations. With appropriate risk assessments, precautions and personal protection measures such as social distancing, Director hygiene measures, reduced density at work and somewhat reduced activity, this has so far gone well with strong efforts from all our employees in these difficult circumstances.

The ICR sets out to maintain the excellent science and outstanding production and to further build excellence by organising more collaborative efforts at all levels to deal with grand challenges in cancer medicine and to position the ICR in national and international alliances and consortia. We aim to be a significant partner for the clinical activities in the Division of Cancer Medicine and the OUS OECI-accredited Comprehensive Cancer Centre (CCC). We continue feeding results into a translational research path and to have patient benefit in mind in all aspects of research and innovation.

April, 2020 Kjetil Taskén, Head of the ICR

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 7 Organisation

e o titte Kei as

ie iitrtie icer Kari arus erger

Administration Service Lab

cer eetic cer oo oecr e ioo oecr coo itio ioo or ioo ore ciitie erese rie oaa eus ara . ear agi . oe Krisia erg ui . aso eoaro . ea-epea

ry aru eii erese rie oaa eus ara ear agi . oe Krisia erg ui . aso ro oe Lab Technology Breast Tumor Initiation Experimental Cellular Membrane Genetics Photochemical Metastasis Biology Flow-Cytometry and Immunotherapy Dynamics Internalization and Experimental Pre-Clinical Imaging Therapeutics uro isae i eii yg ero ioaio Kar-oa aerg orri seri Epigenetics usae ore Clinical Radiation Computational Systems NK Cell Biology and Cancer Molecular Medicine Kersi Faar Genomics and Medicine in Cancer Cell Therapy Biology Translational Cancer Bioinformatics of . oei Therapy or ri use Genome Biology iar ofsa e arpe saug ea ue ee yeus Tumor-host Biology Radiation Biology Advanced Microscopy Translational Studies Lymphoma Biology ii oig and Tumor in Solid Tumors Computational Kirse aig Physiology Cancer Genomics Intracellular Transport essea . Krisese ouy iou ai yuse rge ese Cancer Genome Variation Immunomodulation Radiation Biology Molecular biology (leave of absence and Targeted and DNA Damage of Sarcoma from Q3 2019) Therapies Signaling

ege . . usses Kei as Molecular Biology of Cell Signalling and Breast Cancer Immune Regulation

o u Kye Immunotherapy against solid cancers From 1st of January 2020

8 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 The Institute for Cancer Research Institute for Cancer e o titte Research is organized in 6 Kei as research departments with 25 research groups, and one Department of (6) ie iitrtie icer Core Facilities. Kari arus erger

Administration Service Lab

cer eetic cer oo oecr e ioo oecr coo itio ioo or ioo ore ciitie erese rie oaa eus ara . ear agi . oe Krisia erg ui . aso eoaro . ea-epea

ege . . usses Kei as Molecular Biology of Cell Signalling and Breast Cancer Immune Regulation

o u Kye Immunotherapy against solid cancers From 1st of January 2020

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 9 Key figures 2019

i ter i orce Percent Percent Actual Institute expenditure for 2019 by Sources of external competitive internal and external funding sources funding for 2019, based on actual (total 333,5 MNOK = approx. 32,8 M€) expenditure (total 234,4 MNOK= approx. 23 M€) Internal funding External funding South-Eastern Norway Regional Health Authority The Research Council of Norway The Norwegian Cancer Society University of Oslo EU Other international sources oee Other private sources Other public sources

Female oete D rtice ie Male Key figures ceree First or last authorship Co author Impact factor median

Management Technical Personell PhD students Postdoctors Researchers

oee eer oer oe tot tot tot

2017 2018 2019 2017 2018 2019

M.Sc.-degrees PhDs IMPACT FACTOR

Female Male ICR OUH* UiO Other ICR OUH* UiO Other Mean 5.8 6.5 6.1 Median 4.1 5 4.5 *other than ICR *other than ICR

10 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 i ter i orce Percent Percent Actual Institute expenditure for 2019 by Sources of external competitive internal and external funding sources funding for 2019, based on actual (total 333,5 MNOK = approx. 32,8 M€) expenditure (total 234,4 MNOK= approx. 23 M€) Internal funding External funding South-Eastern Norway Regional Health Authority The Research Council of Norway The Norwegian Cancer Society University of Oslo EU Other international sources oee Other private sources Other public sources

Female oete D rtice ie Male Key figures ceree First or last authorship Co author Impact factor median

Management Technical Personell PhD students Postdoctors Researchers

oee eer oer oe tot tot tot

2017 2018 2019 2017 2018 2019

M.Sc.-degrees PhDs IMPACT FACTOR

Female Male ICR OUH* UiO Other ICR OUH* UiO Other Mean 5.8 6.5 6.1 Median 4.1 5 4.5 *other than ICR *other than ICR

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 11 International Staff Distribution 37 nations are represented 113 people in total are from outside Norway

113

272

n Norwegian: 272 (71%)* n International: 113 (29%) *Including naturalised foreigners 01 InternationalCountries represented by one person Bosnia Colombia Croatia Czech Republic Equador Estonia Finland Ireland Iceland Latvia Macedonia Mexico Netherlands 02 03 04 Pakistan People People People Russia Denmark Austria France Singapore Japan Greece Hungary Slovakia Portugal Iran Switzerland USA Serbia

12 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 International

05 06 07 08 11 13 People People People People People People Great Britain Italy China Sweden India Germany Lithuania Spain Poland

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 13 Oslo University Hospital Comprehensive Cancer Centre

Oslo University Hospital was designated a Oslo Cancer Cluster, - which consist of several biotech Comprehensive Cancer Centre by the OECI in 2017, and pharmaceutical companies. The proximities after a process where activities both in clinical between all these actors, provides an excellent practice and in research were evaluated. The environment for synergies and collaboration. cancer research performed by the Institute for Cancer Research (ICR) is a corner stone in our OECI- Several Centres of Excellence also including basic accredited Comprehensive Cancer Centre (CCC). research are located at the Institute for Cancer Research, enriching the Comprehensive Cancer The Institute is situated in close proximity to clinical Centre with competence and expertise. The extensive cancer departments and diagnostic laboratories international collaboration involving researchers at at the Radium Hospital, a cancer-oriented part of ICR is also an important asset for the CCC. Oslo University Hospital where also the Cancer OsloRegistry of Norway is located. The collaboration Further development of the tight bondsUni between between the ICR and clinical research groups in ICR, clinical researchers and the Cancer Registry, Oslo University Hospital is an important factor to will be important in the coming years and with increase our activities in clinical research. More the new hospital building and proton center that patients into clinical trials is an expressed aim for will open for patients in 2023/24. In the integrated our Comprehensive Cancer Centre, and several organisation of cancer-related activities, the ICR will investigator initiated clinical trials have been be a key participant in the further development of developed in collaboration between researchers at ICR Oslo University Hospital as a leading cancer centre in and clinical research groups at all locations of Oslo Europe. University Hospital. Another of ICR’s neighbours is

Sigbjørn Smeland Åslaug Helland

Head of Division of Cancer Medicine, Research Director, Division of Cancer Medicine Chair, OUH CCC Board Head OUH, CCC Research Committee

14 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Precision Cancer Medicine at OUH Comprehensive Cancer Centre

The implementation of genomic medicine and individualised treatment has been lagging behind in Norway and other countries in Northern Europe with publicly funded health care systems. Against this backdrop, the Head of the Division for Cancer Medicine and Chair of the OUH Comprehensive Cancer Centre appointed a PCM working group1 that started its activities in January of 2019. The working group decided to make a concrete plan for PCM implementation and delivered the results of its work to the Division and the CCC Board in June 2019:

VISION AND OBJECTIVES FOR IMPLEMENTATION OF PRECISION CANCER MEDICINE PROGRESS: • Patients who are referred to OUH with cancer and • In the spring of 2019, the Division for Laboratory where advanced molecular cancer diagnostics will Medicine responded to the needs of the cancer be instrumental for selection of treatment should be area with respect to action points I and II (above) offered such diagnostics at the right time during the and decided to establish a Section for Experi- course of the disease. mental Diagnostics and Research Support in the • Cancer patients should have opportunity to receive Department of Pathology to provide a genomic Oslo Uniindividualised treatment where this is shown to im- medicine platform to ensure delivery of neces- pact on clinical outcome or where it is probable that it sary molecular cancer diagnostics (Head Hege would give patient benefit. Russnes). The CCC PCM working group also on • OUH will learn and build competence in advanced behalf of the CCC in June organized a national molecular cancer diagnostics and individualised treat- meeting on implementation of advanced molecu- ment and contribute to development and production lar cancer diagnostics. and dissemination of knew knowledge in this area. • In the fall of 2020, the PCM working group was ACTION POINTS NECESSARY FOR reinforced and expanded2 and now reports IMPLEMENTATION OF PCM, THREE MAIN AREAS: directly to the CCC Governing Board. The work I. Establishment of a platform that can provide has next focussed on attracting PCM clinical advanced (experimental) molecular cancer trials (action point II). Specifically, the CCC PCM diagnostics. Develop such service also in the working group has looked at the possibility of standard process to examine and diagnose establishing a national PCM trial modelled on the patients. DRUP study in the Netherlands (IMPRESS-Nor- II. Increase the volume of clinical trials and number way trial, national coordinator and PI, Åslaug of patients in trials in the precision medicine Helland) matched by a national infrastructure for area (industry studies, researcher-initiated precision diagnostics, InPreD. The work has in- trials). volved raising national support, discussion with III. Offer individualised cancer treatment in the key stakeholders, planning of a public-private ordinary standard of care in OUH according to partnership with industry participation and na- national and international guidelines. tional consensus as well as organising a second national meeting in January 2020.

1 The Cancer Precision Medicine Working Group (Jan-Sept 2019) has consisted of Kjetil Taskén (ICR, chair) Tormod Guren (Onc), Ragnhild Lothe (ICR), Per Magnus Mæhle (CCC), Hege Russnes (ICR/Pat), Gunnar Sæter (CCC), and with Live Fagereng (ICR) as secretary.

2 From Oct 2019 the CCC PCM Working Group consists in addition to the above members of: Monica Cheng Munthe-Kaas (Ped), Nils Tore Vethe (ClinPharm), Ben Davidson (Pat), Espen Enerly (CRN), Åslaug Helland (Onc/CCC), Yngvar Fløysand (Hem), Kristina Lindemann (GynOnc), Turid Vederhus (Rad), Torunn Berge (HSE, observer)

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 15 Departments

18 Department of Cancer Genetics 26 Department of Cancer Immunology 34 Department of Molecular Cell Biology 40 Department of Molecular Oncology

16 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 46 Department of Radiation Biology 52 Department of Tumor Biology 58 Department of Core Facilities

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 17 “Our mission is to improve the Cancerlives of cancer Genetics patients through translational research in precision oncology” Department of Cancer Genetics Headed by Therese Sørlie

Our aim is to improve risk estimation, achieve earlier vant and metastatic setting diagnosis and improve prediction of treatment responses • EMIT -Establishment of Molecular profiling for Individ- and other clinical outcomes for patients with early and ual Treatment decisions in Early BC; three-phase study advanced stages of both solid tumors and hematologic including randomized and observational clinical trials. malignancies. Our research is translational in nature and • OPTIMA-optimal personalized treatment of early include functional studies, molecular classification, data breast cancer using multi-parameter analysis integration and pan-cancer analyses. We work towards • ComIT - evaluation of the benefit of radiation in combi- facilitating the implementation of discoveries into clinical nation with immune therapy for lung cancer use. A common theme across groups is to achieve a • TREM – Lung cancer patients with EGFR mutations and deeper molecular understanding of inter- and intra- primary TKI-resistance tumor heterogeneity and tumor evolution using patient • ThoRaT - Lung cancer patients receiving radiotherapy cohorts and mouse models. • NorPACT-1 and 2 - Neo-adjuvant chemotherapy for We are an interdisciplinary team of 50 researchers, pancreatic cancer including medical doctors, molecular biologists, • ICON - A randomized phase IIb study evaluating immu- computational biologists and highly specialized nogenic chemotherapy combined with ipilimumab and engineers organized in four research groups and one nivolumab in patients with luminal B breast cancer Cancer Geneticslab-technology unit. Two of the group leaders hold • ALICE – atezolizumab combined with immunogenic part-time clinical positions and three have affiliated chemotherapy in patients with metastatic triple-nega- positions at UiO. The lab technology unit reinforces the tive breast cancer department’s expertise in state of the art technology and • Oslo2- observational study with comprehensive bio- improves exchange of knowledge across research groups banking and cancer types. This is a key asset leading to increased quality of the department’s laboratory work and project We are part of extensive collaborations at the management. institutional, national and international levels, and For translational studies, we have established a partnering in several national and international networks pipeline for high-quality biobanking and secure data and consortia; for instance, the National Breast Cancer handling of patient cohorts with long-term follow-up Research Network, the Norwegian Cancer Society that enables omics analysis of tumors down to single cell expert groups on lung and pancreatic cancer, the levels. Our clinical database consists of > 3000 subjects Regional Research Network on Extracellular Vesicles, from consecutive studies and clinical trials with high Personalized Cancer Treatment and Metaflammation, quality follow-up information. We are involved in the International Cancer Genome Consortium (ICGC), following studies: EuroPDX, the Breast Cancer Association Consortium • NeoAva - Neoadjuvant chemotherapy in breast cancer (BCAC); EU funded projects (EpiMark, Cancer-ID, Gender with/without bevacizumab. Net Plus, HERCULES and RESCUER). The total number of • IBCT - Improved Breast Cancer Therapy in the neoadju- publications in 2019 was 68.

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 19 Department of Cancer Genetics

Breast Tumor Initiation Group Leader: Therese Sørlie

“Understanding cell fate decisions in tumor progression”

ABOUT PROJECTS CancerOur group studies molecular aspects of breast tumor • Characterize breast cancer subtype-specific Genetics initiation and progression with a special emphasis on progression pathways identifying cell(s) of origin of molecular subtypes and • Explore the role of LGR5-expressing cells in the the transition from in situ to invasive breast cancer. The mammary tumorigenesis group counts 10 members, including the group leader • Investigate the role of Hedgehog/GLI1 signaling in and professor (TS), three postdocs , three PhD students, breast cancer progression one master student, and two engineers as well as two • Investigate the role of FOXA1 and FGFR1 in endocrine affiliated scientists (in 20% and 10% positions) and one resistant breast cancer affiliated breast surgeon. Two members are MDs and • Genomic and functional analysis of therapeutic targets one is DVM. We have a broad expertise in laboratory technologies that includes high-throughput genomic RECENT ACHIEVEMENTS technologies, in vivo lineage-tracing, 2D and 3D in 8 publications by group members in 2019. One Master of vitro culture techniques, in situ hybridization, confocal Science completed. microscopy, and FACS analysis. We use patient cohorts and mouse models (transgenic and patient derived xenograft - PDX) in our studies. We also have expertise in bioinformatics and statistical modeling.

AIMS Our aim is to identify the cellular origins of breast tumors and the mechanisms underlying tumor initiation and further development into the heterogeneous molecular subtypes. Through an increased understanding of how early lesions progress to more advances stages, we aim to contribute to improved strategies for early intervention and more precise treatment.

20 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Computational Systems Medicine in Cancer Group leader: Tero Aittokallio

“A systems view of disease networks to pinpoint critical targets and their interaction partners”

ABOUT PROJECTS CancerThe group wasGenetics launched in September 2019 when Tero • Multi-omics prediction of clinical outcomes for Aittokallio moved from Finland (FIMM, University precision oncology applications of Helsinki and University of Turku). Our group has • AI-guided treatment optimization by means of expertise in integrating multi-omics profiling and clinical cost-effective biomarker panels information from cancer patients using mathematical • Decision support systems for real-time patient and statistical approaches, such as machine learning monitoring and adaptive trials and network modeling. We carry out multidisciplinary projects in collaboration with other researchers from the RECENT ACHIEVEMENTS institute and as part of international projects, where we In 2019, the group published 11 articles in peer-review develop, test and implement novel practices of how to journals and 2 book chapters. We are partnering in use artificial intelligence (AI) and machine learning (ML) several international translational projects, including models in translational and clinical studies. We believe ERA-PerMed project JAK/STAT TARGET, EU-H2020 that combining functional, molecular and genomic project HERCULES, and the UK Breast Cancer Now profiling information is critical for next-generation Catalyst Programme for predictive markers for TNBC precision medicine applications, where integrative drug responses. In 2019, the group received 3-year modeling and clever use of patient-level big data will open-project grant from South-Eastern Norway Regional pinpoint effective and selective targets for personalized Health Authority for AI-guided treatment optimization therapies. by means of multi-omics biomarker panels.

AIMS The modeling aim is to develop novel supervised learning approaches to identify multi-omic features predictive of clinical outcomes for individual patients by means of efficient AI/ML models that maximize the accuracy of outcome predictions using minimal panels of biomarkers. The medical aim is to optimize treatment outcomes for individual patients using the maximally predictive models and minimal biomarker signatures that enable real-time and cost-effective diagnostics and prognosis.

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 21 Department of Cancer Genetics Translational Studies in Solid Tumors Group leader: Åslaug Helland

”With starting point in clinical studies and clinical questions, we do molecular analyses aiming at improving outcome for cancer patients”

CancerABOUT PROJECTS Genetics Our group focuses on translational studies on solid • Molecular characterization (-omics) of pancreatic- and tumours, with a special interest in pancreatic, lung and lung cancers colorectal cancers. By increasing the understanding of • Proteogenomic analysis of pancreatic tumors and the underlying biology of tumour development, we will characterization of circulating biomarkers in free plas- improve precision medicine in cancer care. Several of ma and exosomes our projects include material from patients included in • Identification of circulating plasma biomarkers in clinical studies, and we have detailed clinical data from colorectal cancers (the Nordic VII clinical trial) all patients. Predictive biomarkers and mechanisms of • Protein (TMA) analyses in lung cancers resistance is in focus. • Serum predictive markers for therapy response • Elucidate mechanisms for therapy resistance We are organized into three project groups, headed • Expand biomarker identification material to stool (mi- by Elin H. Kure (Professor USN), Odd Terje Brustugun crobiome) and urine and Åslaug Helland (Professor UIO) , with a total of • Investigate combination of radiotherapy and immuno- 17 members. Seven of these are MDs. We are three therapy researchers, three postdocs, seven PhD-students, one • Gender differences in side effects on immunotherapy study nurse and three engineers. RECENT ACHIEVEMENTS AIMS In 2019, the group published 18 papers in peer-reviewed The ultimate goal is to increase our ability to offer journals. We have had several talks at national and personalised cancer treatment, and thereby improve international meetings, and are PIs on >20 translational prognosis. and clinical studies. An ERA-network we are part of received funding (Gender-net). We are partners in Sub aims are: several South-Eastern Norway Regional Health Authority • Identification of biomarkers in blood samples, for diag- networks (NORSMAN, ReMics, NIRO), and received nostics, follow-up and prognostication approximately 36.2 mill NOK in research funding (Elin • Identification of tumour biomarkers for prediction of Kure 1.2 mill, Odd Terje Brustugun 2 mill, Åslaug Helland therapy response and for prognostication 33 mill).

22 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Cancer Genome Variation Group leader: Vessela Kristensen

“Germ-line and somatic genetic and epigenetic variants in cancer and pharmacogenomics”

CancerABOUT Genetics• Genome variation: In the breast cancer association The Kristensen group with 2 senior scientists, 3 postdocs, consortium we identified 160 new breast cancer risk 2 PhD students, 1 MSc and 2 research technologists loci (published in Nature Genetics) and contributed to moved Q3-2019 to Institute for Medical Genetics (IMG) the fine-mapping of these loci (credible causal variants at OUH. The group will continue to work towards CCV). intensive and fruitful collaboration between ICR and IMG • Epigenomics of Breast Cancer: Identification of epige- and with the Institute for Clinical Medicine, University netically regulated cancer-driving pathways in breast of Oslo. Group members work closely together and in cancer, and functional validation using CRISPR epige- collaboration with breast clinicians, pathologists and netic engineering. oncologists. A remaining project group at ICR consists of • MicroRNAs in breast cancer: Alterations in miRNA 1 senior scientist and 3 PhD students. This project group expression caused by neo-adjuvant treatment with is headed by Thomas Fleischer (Epigenomics of Breast chemotherapy and bevacizumab is associated with Cancer) and works to characterize epigenetic alterations proliferation and response to therapy (published in in breast cancer, and assess the implications for breast Molecular Oncology). Identification of miRNAs as po- cancer pathogenesis and utilization for precision tential master regulators of the methylome in breast medicine (http://ous-research.no/fleischer). cancer. • Non-canonical transcriptomes: Characterization of AIMS alternate exon usage and long non-coding RNA ex- The Cancer Genome Variation group is working to pression in breast cancer and connection to epigenetic understand how genetic variation affects occurrence profiles and patient outcomes. of somatic alterations, gene expression patterns and • Immune signaling: Identification of patient groups genome wide copy number alterations in human based on immune signaling identifies a bad prognosis tumours (http://ous-research.no/kristensen/) immune infiltration type independently of PAM50 classification and other known clinicopathological PROJECTS features (published in Nature Communications) Together with our collaborative network we received several major grants in 2019: from EU Horizon 2020 RECENT ACHIEVEMENTS (RESCUER: 63 mill NOK), EU EraCoSysMed (PI, 3 mill Publication activity. 22 publications in 2019, popular at NOK), South-Eastern Norway Regional Health Authority https://radiumlegat.no/Prosjekter/Vessela-Kristensen, (Open Project, 9 mill NOK; PhD student, 3 mill NOK). Projects include:

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 23 Department of Cancer Genetics Molecular Biology of Breast Cancer Group Leader: Hege G. Russnes

“Exploring inter- and intra-tumor heterogeneity to improve molecular classification of breast cancer”

ABOUT PROJECTS The group was founded January 2018 and have a total of • LATE: Characterizing in time and space the metastatic 2 scientists, 1 postdoc, 1 research engineer, 1 nurse/MSc, process of hormone receptor positive breast cancer Cancer1 MD-PhD student and 1 MD student. In addition, 1 prof. • TREAC: Towards personalized treatment for patients Genetics emerita (A-L Børresen-Dale, UiO), 1 researcher (group with aggressive breast cancer leader A. Matheliér, NCMM), 1 oncologist (L. Ottestad) • Somatic Genetics of Breast Cancer, from single genes and 1 professor in bioinformatics (O. C. Lingjærde, UiO) to whole genome sequencing are associated with the group (part-time). • SN - Sentinel Lymph Node in Breast Cancer- reveal- Focus of the group is to reach a more fundamental ing the interaction between tumor subtypes and host understanding of the biological dynamics of breast immune response. cancer through high-throughput molecular analyses of • CANCAN: CANcer specific Copynumber alteration DNA, mRNA, miRNA and protein, both at diagnosis and Analysis during disease progression. • CARMA: Copy Aberration Regional Mapping Analysis As co-PI/partners in several clinic trials we perform • Liquid biopsies – optimizing methodologies for nucleic “state of the art” analyses of patient material, both on acid and single cell detection, capture and analysis bulk tumors, single cells and liquid biopsies, at various stages of the disease. The group is active in the IMI/EU RECENT ACHIEVEMENTS funded project CancerID aiming at standardizing liquid In 2019 we published 9 articles in peer-reviewed journals biopsies for cancer diagnostics. Hege G. Russnes is also (in addition to 19 publications by our affiliated members). senior consultant at Dept. of Pathology, OUH where The LATE project received major funding from South- she is Head of “Section for experimental pathology and Eastern Norway Regional Health Authority (open project research support”, a lab developing and performing support) and from the Wellcome Sanger Institute (coll. molecular diagnostics for clinical trials. She is also MD/PhD Lucy Yates). The TREAC project, a collaboration appointed “Young Associated Investigator” at NCMM with Elin Mortensen (University of Northern Norway), (Centre for Molecular Medicine Norway). received a generous grant from Jeanette and Søren Bothners legat. In addition to being active partners in AIMS several clinical trials (ICON, ALICE, OPTIMA, I-BCT) we Our group aims at defining, refining and implementing are coordinating the EMIT trial (A. Langerød). The EU/ molecular classification and biomarker analyses to IMI collaboration CancerID finished December 2019, and improve stratification of cancer patients into treatment we are active partners in the initiation of The European relevant groups. We are addressing the impact of inter- Liquid Biopsy Society (ELBS). and intra-tumor heterogeneity as well as host response on disease progression, response to therapy and patient outcome.

24 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Cancer Genetics

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 25 “Our goal is to improve cancer diagnostics and therapy through cutting edge research on tumor immunology and Cancerlymphocyte biology” Immunolo- Department of Cancer Immunology Headed by Johanna Olweus

ABOUT • Therapeutics, by The Department of Cancer Immunology (DCI) consists of – genetically engineered T and NK cells five research groups (Olweus, Taskén, Sioud, Myklebust, – immune priming with siRNA and antigen-targeting Malmberg) and one project group (Kyte). Four DCI to DC members are full professors at the University of Oslo. – genetically engineered human antibodies and lytic Groups at the DCI are partners in two K.G. Jebsen Centers peptides (Cancer Immunotherapy and B-cell malignancies) – cell therapy across HLA barriers to overcome and several EU-funded research programs in cancer immune tolerance immunotherapy. The groups provide complementary – clinical trials using experimental immunotherapy expertise in molecular and cellular immunology, – small molecules including a broad experimental tool-box for antigen discovery and studies of immune cells at the single cell RECENT ACHIEVEMENTS (2019) level. The aim is to decipher the molecular regulation • 27 publications; 70% with first/last authors from of key cellular components of the innate and adaptive DCI (mean/median IF 10.1/6.4), including first and/or immune system, including dendritic cells (DC), B cells, senior authorships in high-impact journals like Nature Cancer ImmunoloT cells, regulatory T cells (Treg) and NK cells. The Communications, Nature Protocols, Cell Reports, - key driving force is to develop better tools for cancer Leukemia and Haematologica diagnostics and new therapeutic strategies. The latter • Awarded ERC Consolidator Grant (2 mill Euro) to include investigator-initiated clinical trials to alleviate Olweus for the project “Outsourcing Cancer Immunity immune suppression and improve the use of check-point to healthy donors” (only scientist in Life Science inhibition, and the design of gene-edited T- and NK cells category in Norway) for adoptive cell therapy. • Launched Strat-Cell, a strategic research program (5 years) in cell therapy at Oslo University Hospital PROJECTS (Malmberg Director, Olweus/Kyte co-Directors) • Lymphocyte biology, by deciphering • Filed four new DOFIs, three patent applications filed – ontogeny and function of B, T and NK cells and two granted. – tumor heterogeneity (signaling and mutanome) • 1 graduated Msc – immune cell recognition elements (antigen discovery) CLINICAL TRIALS: • Biomarkers, by profiling of • Recruited first 300 patients to the ASAC trial that – lymphocyte repertoires examines the effect of reversing prostaglandin E2- – the tumor and its microenvironment mediated inhibition of tumor immunity in patients – T-cell receptors and humoral immunity with metastatic colorectal cancer by the end of 2019 (www.asac.no)

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 27 Department of Cancer Immunology Experimental Immunotherapy Group leader: Johanna Olweus

“Overcoming tolerance by T-cell based cancer immunotherapies”

ABOUT PROJECTS The group counts 16 members (F/M 70/30); 1 full Strategy 1 professor (JO), 6 postdocs, 5 PhD students and 3.5 • Identification of novel TCRs targeting self-antigens Cancerengineers, and two associated clinicians. Four members and epitope discovery Immuno have MD background. 13 members are recruited from Strategy 2 abroad. The group is partner in K.G. Jebsen Center • Identification of novel TCRs targeting neoantigens and for Cancer Immunotherapy (2013-); (JCIT). Olweus epitope discovery is Director of JCIT, which was awarded maximal • Characterization of anti-tumor reactive T cells in prolongation in 2016 (two years), till 2020 biobanked material from patients responding to immunotherapy AIMS To find new immunotherapeutic T-cell based strategies RECENT ACHIEVEMENTS that overcome the major challenge of self-tolerance Olweus was awarded an ERC Consolidator Grant (2 in cancer, and couple clinical trials with penetrating mill Euro over 5 yrs), as the only Norwegian scientist mechanistic analyses. Two principally distinct in the Life Science category. The group described a approaches are pursued in an interdisciplinary and technology for identification of neoantigen specific T translational program: cells from healthy donors (Ali/Foldvari/Giannakopoulou Strategy 1: Use of T cell-based alloreactivity to target self- et al, Nature Protocols, 2019), and wrote an invited antigens. perspectives article for Blood (Olweus and Lund- Strategy 2: Identification and targeting of cancer-specific Johansen, 2019). The group continued their research neo-antigens. collaboration with biotech company Kite Pharma (acquired by Gilead) on development of T-cell receptors to target cancer. Olweus was elected member of the Executive Board of CIMT, organizing the largest and most influential annual cancer immunotherapy meeting in Europe. She was invited speaker at numerous international conferences in 2019, including the CIMT Winter School in immunology (Innsbruck), Synthetic Systems Immunology (Ascona), MDS Symposium (Copenhagen), Cancer Research UK Symposium (London).

28 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 NK Cell Biology and Cell Therapy Group leader: Karl-Johan Malmberg

“Towards the next generation NK cell therapy”

ABOUT PROJECTS The Malmberg Lab in Oslo counts 18 members (F/M: 1) Functional Diversification of human NK cell repertoires 10/8); 1 full professor (KJM), 2 scientists, 1 project 2) Cell therapy with iPSC-derived NK cells Cancermanager, 7 postdocs,Immuno 5 PhD students, 3 engineers. Malmberg is a visiting Professor at the Karolinska RECENT ACHIEVEMENTS Institute (KI) and a partner in the K.G. Jebsen Center • Gained new insights into the functional regulation of for Cancer Immunotherapy. Affiliated to the group human NK cells (Goodridge et al, Nature Communications is the Kyte Project group in Translational Cancer 2019) Immunotherapy led by Dr. Jon Amund Kyte, with 10 • Deciphered molecular pathways involved in NK cell members: Project group leader (JAK), 3 researchers, two homeostasis (Jacobs et al., J Immunology 2019, Pfefferle et postdocs, 1 MD PhD student, 3 technicians. Dr. Kyte is al., Cell Reports 2019) also a senior consultant in oncology and Head of Dept. • Completed a one-year research sabbatical at UCSD Clinical Cancer Research and is appointed Group Leader resulting in new collaborations with world leading at DCI from 2020. iPSC environments (Sætersmoen et al., Seminars in Immunopathology 2019). AIMS • Launched Strat-Cell, a strategies research program (5 The Malmberg group seeks to develop new strategies years) in cell therapy at Oslo University Hospital. for cell-based immunotherapy based on insights into • Innovation: Initiated a 2-year collaborative agreement the functional regulation of natural killer (NK) cells. with EMD-Serrono to develop functional modulators A combination of single-cell assays, including live of NK cells in vivo. cell imaging, high-dimensional immune profiling by mass cytometry, flow cytometry and RNA-seq is used to decipher the cellular and molecular mechanisms involved in calibration of effector functions in human NK cells. The Kyte group aims to develop improved cancer treatment based on two strategies for immunotherapy: 1) Development of cell therapy by use of novel tumor- targeting chimeric antigen receptors (CARs) and concepts for countering tumor tolerance 2) Development of optimized regimes for combining checkpoint inhibitors with chemotherapy or radiotherapy. The Kyte group has from 2017 started three clinical trials, in breast cancer (ALICE, ICON) and head and neck cancer (REPORT).

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 29 Department of Cancer Immunology Lymphoma Biology Group leader: June Helen Myklebust

“Understanding B-cell lymphoma biology to identify new therapeutic targets and treatment strategies”

CancerABOUT • Clonal evolution and recurrent mutations associated Immuno The group counts 13 members with research background with therapy relapse in medicine, biology and biotechnology, and includes 1 • Functional characterization of recurrent driver professor, 1 associate professor, 1 scientist, 7 postdocs mutations (including visiting postdoc at MGH/Broad Institute, • Novel targets for immune checkpoint blockade Boston), 2 PhD students and 1 technician. Five members • Cancer sensitivity drug screen and preclinical testing have MD background and four members are recruited • Clinical register studies from abroad. The group is part of the KG Jebsen Centre for B-cell malignancies. RECENT ACHIEVEMENTS The group published 7 original papers, 1 commentary AIMS: and 1 news&views (Nature) in 2019: Our in-depth The group performs translational studies in B-cell analysis of the tumor microenvironment identified TIGIT lymphoma to define tumor clonal evolution, cancer and PD-1 as relevant targets for co-checkpoint blockade driver genes, actionable targets and new targets for in B-cell lymphoma (Josefsson, Cancer Immunol Res). immunotherapy. Our collaborative effort with Cell therapy has led to preclinical development of CD37 CAR T cell therapy PROJECTS (Köksal, Blood Adv and patent filed). We developed the We use single-cell technologies to characterize tumor clinical-genetic prognostic tool BTK-FLIPI to identify cells and intratumor immune cells in patient biopsies. follicular lymphoma at high risk for adverse disease This includes high-dimensional flow cytometry, mass (Steen, Haematologica), and contributed to convergence cytometry and mass cytometry imaging (Hyperion), and of risk prediction models (Silva, Haematologica). Several single-cell RNA sequencing. We also use CRISPR/Cas9 members had oral presentations at international genomic editing combined with immunological assays meetings; the most prestigious being our collaborative to characterize potential cancer driver genes, and have project with lymphoma clinicians, the Hovig group and established patient-derived xenograft (PDX) mouse Genomics core facility to map tumor clonal evolution in models for pre-clinical drug testing. Ongoing projects follicular lymphoma, selected for oral presentation at the are: American Society of Hematology (Bai, ASH 2019).

30 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Immunomodulation and Targeted Therapies Group leader: Mouldy Sioud

“Innovative approaches for cancer therapy”

CancerABOUT ImmunoPROJECTS The group has 8 members, including 1 postdoc, 2 • Profiling the cell surface proteome using high- research engineers, 1 PhD student, 3 master students, throughput phage display technologies and the group leader (DEA Pharm, PhD) with formal • Development of therapeutic human antibodies and research experience in immunology, molecular and cell lytic peptides biology, microbiology, and medicine. Sioud is a visiting • Fingerprinting immune responses in cancer patients professor at University of Tunis. To date, the group has • RNA interference and CRISPR technologies as immune published 197 peer-reviewed original articles (mean IF modulators = 5.865) and reviews, with 1st and/or last authorship on 85% of the papers. RECENT ACHIEVEMENTS • Reported the first lytic peptide targeting tumor Traditional cancer treatments like radiation and macrophages and leukemia cells (Sioud et al. Cancers chemotherapy have major side effects because they not 2019) only affect the tumors, but also the healthy parts of the • Developed new antibody-photosensitizer conjugates body. Hence, there is a need for improvement. The group to target and kill cancer cells (Gebretensaie et al. is mainly focused on the development of therapeutic manuscript in preparation) antibodies, lytic peptides, and small RNA modulators • Developed new human antibodies to modulate to target and kill cancer cells or counteract immune immune cell functions suppression. With respect to clinical translation, we • Described a new mechanism of action of developed the first RNA interference-modified dendritic extracorporeal photopheresis immunotherapy cell cancer vaccine that is now available to patients involving IDO+ tolerogenic dentritic cells (Sagar et al. under compassionate use (Sioud 2019, Cancers, IF 6.2). Cancers 2020). • Three publications AIMS • Sioud edited a new book on RNA interference and The principal aim is to develop antibodies, antibody CRISPR technologies (Springer-Nature: https://www. derivatives (e.g., antibody-photosensitizer conjugates, springer.com/gp/book/9781071602898). chimeric antigen receptors, bispecific antibodies), and • The group obtained funding from South-Eastern lytic peptides for use in cancer immunotherapy. Norway Regional Health Authority and Radforsk

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 31 Department of Cancer Immunology Cell Signalling and Immune Regulation Group leader: Kjetil Taskén

«We want to perturb tumor immune evasion Cancermechanisms to boost anti-tumor immunity» Immuno ABOUT PROJECTS In 2019 the group counted 18 members (F/M: 10/8), 1 • T cell function in cancer and immune-related diseases full professor (KT), 1 senior consultant, 2 researchers, 8 • Identification of regulatory T cell targets that can be postdocs, 1 PhD student, 1 MD/PhD student, 2 technicians perturbed to reverse tumor immune suppression and 2 M.Sc. students. The group is part of K.G. Jebsen • Role of Prostaglandin E2, cAMP and AKAPs in Centres for Immunotherapy and B Cell Malignancies. signaling and regulation of T cell function • Targeting the cAMP signalling pathway for cancer AIMS immunotherapy The Taskén group aims to understand intracellular • CDSS in chronic lymphocytic leukemia and multiple signalling networks, the anchoring and localization of myeloma, understanding drug synergies and signaling complexes through scaffold proteins, how predicting effective drug combinations in individual these signalling networks mediate physiological and patients (RCN-Digital Life PINpOINT project) pathophysiological processes and can be perturbed using • Acetyl salicylic acid clinical intervention study in drug-like small molecules. We aim to understand tumor metastatic colorectal cancer (ASAC) immune evasion mechanisms, and how we can interfere to boost anti-tumor immunity. We proceed with cancer RECENT ACHIEVEMENTS drug sensitivity screening (CDSS) to explore individual Publication highlights include studies on CLL patients in drug responsiveness and resistance patterns in patient our precision medicine programme where we predict cancer cells and aiming to develop models to assist clinical dosing of combinatorial treatments based on individualised clinical decisions in precision medicine in biomarker studies (Leukemia), on regulatory T cells and oncology and haematology. tumor immune suppression by idelalisib (J. Immunol.) and on signalling complexes orchestrated by CD28 and CD2 (J. Immunol.). Furthermore, in co-authored papers we have contributed to understanding metabolic regulatory programmes for aerobic glycolysis in T cells (Nature) and TLR8 signaling in T cells (Nature Commun., in press). 1 DOFI was submitted, 1 patent was filed and 1 granted. One M.Sc. student graduated.

32 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Cancer Immuno

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 33 “Uncovering the cellular basis of cancer development” Molecular Cell Department of Molecular Cell Biology MolecularHeaded by Harald Stenmark Cell The department has a staff of 80 (including 11 MSc and tumour growth, growth factor signalling and students and trainees) of 23 nationalities and hosts intracellular transport, molecular mechanisms of cell 4 research groups (Enserink, Rusten, Sandvig and division, exosome secretion and biomarkers for prostate Stenmark), 9 project groups, and a departmental cancer. In general, the department’s groups have been service unit. Research in the department comprises successful in obtaining national and international various aspects of cancer relevant cell biology, including external funding. membrane traffic, cell signaling, cell metabolism and cell division. In addition, the department carries The groups of Harald Stenmark, Jorrit Enserink and out biotechnological research on nanoparticles and Tor Erik Rusten are members of a Norwegian Centre translational research on leukemia drug sensitivity, of Excellence, CanCell, headed by Harald Stenmark. cancer-related fungal infections, and cancer derived Harald Stenmark also heads the Norwegian Advanced exosome biomarkers. Light Microscopy Infrastructure Network, NALMIN, and the Chinese-Norwegian Partnership for Education and A common goal for researchers in the department is Research in Cancer Cell Biology, ChiNoCell. Stenmark’s to uncover novel molecular mechanisms that control group is member of a Convergence Environment cellular functions related to cancer. The department’s under UiO Life Science, called “Programmable cell-like research strategy is to combine molecular cell compartments”. Jorrit Enserink participates in a project biology with biochemistry, genetics, drug screening under Norwegian Centre for Digital Life, “Pipeline for and advanced imaging in order to address relevant individually tailoring new treatments in hematological scientific questions. Recent key achievements from the cancers”. Enserink’s group also participates in the EU department’s scientists include studies on autophagy Horizon 2020 project, RESCUER.

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 35 Department of Molecular Cell Biology Cellular Membrane Dynamics Group leader: Harald Stenmark

“Understanding how remodelling of cellular membranes contributes to cancer”

ABOUT RECENT ACHIEVEMENTS The group studies the dynamics of cellular membranes • New mechanism of tumour suppression – intracellular Molecularwith the aim of understanding their relevance to cancer. retention of matrix metalloproteinases (Sneeggen Cell Cellular membrane dynamics processes studied by the et al., Nature Communications 2019). Awarded group include endocytosis, autophagy, and cell division. publication prize from Oslo University Hospital. The group has 34 members from 12 nations and is • ESCRT proteins promote autophagy by mediating headed by Harald Stenmark (group leader) and Camilla sealing of newly formed autophagosomes (Zhen et al., Raiborg (assistant group leader). Its 5 project groups are Autophagy, 2019). led by Andreas Brech, Kaisa Haglund, Camilla Raiborg, • Novel mechanism for recruitment of the abscission Kay O. Schink, and Antoni Wiedlocha. machinery to the midbody during cytokinesis – (Lie- Jensen et al., Current Biology, 2019). Dedicated a AIMS commentary article in Current Biology. The principal aim of the group is to understand how • Comprehensive review on ESCRT proteins in sealing membrane dynamics contribute to tumour suppression and scission of cellular membranes (Vietri et al., and how their dysfunction may promote cancer Nature Reviews Molecular Cell Biology, 2019). development. • Major grants in 2019 to Kay O. Schink, Harald Stenmark, and Viola Nähse. PROJECTS • Marte Sneeggen obtained her PhD in November 2019. • Phosphoinositides in regulation of membrane dynamics • Harald Stenmark was invited speaker at international • Mechanisms of autophagy and lipid droplet biogene- conferences in Okinawa, Paris, Trondheim, Glasgow, sis, and their role in cell metabolism Beijing, Edinburgh, Essen and Strasbourg in 2019. • Centrosome dynamics in cancer • Nina Marie Pedersen and Lene Malerød were selected • Cytokinesis in development and carcinogenesis for oral presentations at the international conference • The β-catenin destruction complex in physiology and on “Cell Signaling and Intracellular Trafficking in cancer Cancer Biology” in Turin, and Yan Zhen and Andreas • Membrane dynamics in promotion of genome integrity Brech received prizes for best posters at the 9th • Mechanisms of cancer cell invasion International Symposium on Autophagy in Taipei. • New collaboration on cancer cell invasion, InvaCell, with the group of Philippe Chavrier at the Curie Institute, Paris. InvaCell is generously sponsored by Trond Paulsen. • Members of the group published 13 original papers and 3 reviews in 2019.

36 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Cancer Molecular Medicine Group leader Jorrit Enserink

“Identifying weak points in the molecular networks that drive cancer”

ABOUT • Development of novel immune therapy for AML The group currently consists of one group leader, two • Modeling of leukemia in fruit flies to better Molecularproject group leaders, seven post-docs, one clinician in understand theCell genetic networks that drive AML a 20% post-doc position, two PhD students, four MSc • Genome-wide CRISPR-Cas9 screens in leukemic cells students and one Erasmus student. A large fraction of to identify novel mechanisms of resistance to tyrosine the group consists of scientists from abroad , including kinase inhibitors the Netherlands, Austria, Spain, Colombia and the UK. • Cellular responses to nutrient stress; particularly the The group is mainly focused on basic cancer biology and identification of the upstream pathways that control personalized medicine, using a wide range of models the dynamics of autophagy such as budding yeast and fruit flies, human and mouse cell lines, and primary human cancer samples. ACHIEVEMENTS AIMS • Five MSc degrees were completed and the group Research is aimed at understanding cancer cell biology, published three articles. with the ultimate goal of developing precise cancer treatments. A major focus is on hematopoietic cancers, • Funding obtained: A research grant from The including –but not limited to– Acute Myeloid Leukemia Norwegian Cancer Society to Jorrit Enserink and (AML). A second research theme is to better understand a Young Research Talent grant from The Research cellular responses to sudden environmental changes. Council of Norway to Dr. Helene Knævelsrud.

PROJECTS • High-throughput drug combination screens to identify • The group is also part of the RESCUER project headed drug synergies and to reveal correlations between by Dr. Vessela Kristensen, which was awarded by the driver mutations and drug sensitivity profiles EU Horizon 2020 scheme in 2019.

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 37 Department of Molecular Cell Biology Tumor-host Biology Group leader Tor Erik Rusten

“Tumor-host interactions during cancer progression”

ABOUT AIMS The research group counts 12 members representing The principal aim of the group is to understand tumor- 7 nationalities in 2019 (Australia, India, Iran, Hungary, host interactions that facilitate cancer progression in MolecularFrance, Spain and Norway): 1 group leader, 1 scientist, 5 order to uncover novel ways to intercept cancer. Cell postdocs and 1 PhD student, 1 technician and 1 master students and 2 Erasmus exchange students. PROJECTS Cancer can be regarded as organ development • Oncogene-induced epithelial disintegration and inva- derailed. Our overarching interest is to understand the sion. mechanisms by which tumor and host cells mutually • Tumor-microenvironment interactions and growth engage each other in reciprocal interactions that promote support. cancer progression. These interactions occur locally • Mechanisms of cancer cachexia. in the tumor microenvironment, but also systemically • Roles of autophagy in metabolic reprogramming, causing organ dysfunction such as in cancer cachexia - nutrient mobilization and breakdown of muscle and the catastrophic wasting of muscle and adipose tissue. adipose tissue during cancer cachexia. We believe that studying these processes can uncover new ways to intercept carcinogenesis. To mechanistically RECENT ACHIEVEMENTS probe how tumor cells and non- tumor cells and organs • EMBO long-term postdoctoral fellowship was award- communicate to foster tumor growth and cause cancer ed to Dr. Swarupa Panda to work on “Mechanisms of cachexia we develop novel genetic tools in Drosophila. non-autonomous support of tumor cell growth” These tools will allow us to selectively and independently • Tor Erik Rusten was invited at 5 international research manipulate tumor and either tumor microenvironment conferences (including a Gordon Research Conference) or somatic organs in vivo. We investigate the molecular in Heidelberg, Lisbon, Utrecht, Barcelona and Santa Fe genetic mechanisms and cell biology of genetically in 2019, one of these as keynote speaker defined experimental tumor-host interactions using a • In 2019 one MSc was completed and the group pub- mix of human cell culture and the fruit fly Drosophila lished one review, one preview and contributed to two melanogaster, as an animal model system. In this work original research articles we employ a wide array of techniques and collaborate with experts in cell biology, genetics, imaging, electron microscopy, tumor biology, metabolism, bioinformatics and clinical cancer cachexia in order to survey, measure and mechanistically understand these complex aspects of cancer biology.

38 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Intracellular Transport Group leader: Kirsten Sandvig

“All the way from basic research to translation”

ABOUT AIMS Sandvig’s group, counting 15 members, is interested in The projects aim at increasing our knowledge about the mechanisms of endocytosis, intracellular transport intracellular transport, nanoparticles for drug delivery, Molecularand secretion. Uptake of receptors and ligands and correct and exosomal biomarkersCell in order to provide a rational intracellular sorting of endocytosed molecules are crucial basis for diagnosis, treatment and prevention of cancer. for maintenance of a normal differentiated phenotype. In some studies we are using protein toxins such as ricin PROJECTS and Shiga toxin, which are well established as markers • Characterization of intracellular transport for studies of membrane traffic, and which can be used • Biodegradable nanoparticles in cancer diagnosis and as agents in cancer diagnosis and therapy. Our expertise therapy is also applied to investigate uptake of nanoparticles for • Exosomes and prostate cancer drug delivery, and since 2013 we have had a large grant from the Norwegian Research Council to build national RECENT ACHIEVEMENTS competence in nanomedicine. This project, “Biodegradable • Mechanistic studies of different types of endocytosis nanoparticles in cancer diagnosis and therapy”, headed by and intracellular transport. Our competence Sandvig, involved collaboration with ten other Norwegian concerning cellular membranes and lipid species groups working in academia, research institutes, hospitals made us publish a perspective article (Skotland et and industry, and was running until March 2019. The al., Nature Communications, 2019) about the role Sandvig group has also been involved in an INNO INDIGO of specific lipid species and what should be done in granted project, which started April 2016 and ended the future to increase our understanding of cellular September 15th, 2019. INNO INDIGO is an innovation- membranes. driven initiative for the development and integration of • We have performed further studies of exosome Indian and European research. Our nanoparticle research biogenesis and release, as well as of biomarkers for has, based on results from these projects, obtained further prostate cancer. Investigations of cytotoxic effects support from the Norwegian Cancer Society for 2020- of different types of nanoparticles with and without 2023. We also characterize exosomes from prostate cancer drugs were performed both in vitro and in vivo. cells and patients with the goal of detecting lipid, RNA • In 2019 the group published on the different topics; 10 and protein biomarkers. Our research spans all the way articles in different journals. from basic to translational medicine, including innovation. • Kirsten Sandvig obtained a research grant of 8 MNOK The work published by the Sandvig group is well cited, from the Norwegian Cancer Society on a project and Sandvig’s H-index is now 73 (~340 publications). that will investigate the efficacy of drug-containing The group has extensive national and international nanoparticles in breast and colorectal cancers. collaborations.

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 39 ”Biological discoveries for improved precision cancer Molecularmedicine” Oncology Department of Molecular Oncology Headed by Ragnhild A. Lothe

Our main research programs are devoted to colorectal A few selected results from last year: cancer and prostate cancer, but with a longstanding We showed that multifocal primary prostate cancers project portfolio also on other solid tumor types. Our have an exceptional degree of intra-patient genomic expertise in biomedical research spans across several heterogeneity (Løvf et al., Eur Urol), and this challenges disciplines, and we have a broad range of advanced the usefulness of known molecular classifiers technologies and analytical tools established in the lab. (Carm et al., Sci Rep). Furthermore, we published a The department hosts three research groups and three comprehensive review on biomarker-guided therapy project leaders, in total ~10 % of the total staff at the for colorectal cancer (Sveen et al., Nature Rev Clin Institute (full time equivalent). Six of the senior scientists Oncol), and demonstrated the clinical impact of tumor are affiliated with the University of Oslo as professors microenvironment markers relative to cancer genomic (three), associate professor, or lecturers (two). We are markers in patients with colorectal cancer (Dienstmann Molecular Oncologydevoted to teaching and supervision, and six academic et al., Ann Oncol; Berg et al., Oncogene). degrees (4 MSc and 2 PhD) with main supervisors from A national multicentre study and innovation project to our Department were successfully completed last year. monitor bladder cancer patients with cancer-specific epigenetic markers in urine samples documented strong Our research groups are current partners of the K. G. discovery and validation results (unpublished), and Jebsen Colorectal Cancer Research Centre, an OUH externally financed by major grants from the Norwegian Strategic Research Area, and several national and Research Council and National Health Regions international scientific networks. The latter includes (KLINBEFORSK) national multicenter studies on colorectal cancer and bladder cancer, European cooperation studies on Our main research goals for the next three to five years colorectal cancer (COST action), a European multicenter are three-fold, (i) to decipher spatio-temporal tumor study on the rare tumor type malignant peripheral heterogeneity and its clinical relevance in colorectal nerve sheet tumor, the European network for study on cancer and prostate cancer, (ii) to monitor minimal cholangiocarcinoma, and the Global Testicular Cancer residual disease, early recurrence and clonal evolution by Consortium. analyses of repeated liquid biopsies and tumor samples, and (iii) to predict treatment responses by combined molecular profiling and ex vivo drug screening of patient- derived organoids in clinical trials and translational studies.

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 41 Department of Molecular Oncology Genetics Group leader: Ragnhild A. Lothe

“Molecular tumor heterogeneity and personalized pharmacogenomics - the basis for next generation clinical trials”

ABOUT MolecularOur main research program involves translational We published a comprehensive review on biomarker- Oncology studies of primary and metastatic colorectal cancers guided therapy for CRC (Sveen et al., Nature Rev Clin (CRC), using genomics, drug screening, digital pathology Oncol 2019), showed that splice variants of KRAS and functional analyses. The group has 23 members has prognostic relevance beyond its mutation status and includes two project groups in Cell signaling and (Eilertsen et al., Int J Ca 2019) and we concluded that Computational oncology. the long noncoding RNA MIR31HG is a bona fide prognostic marker in CRC (Eide et al., Int J Ca 2019). We AIM showed that TP53 mutations may modulate the immune Our overarching goal is to translate novel biomedical microenvironment in a particularly immunogenic knowledge into improved patient stratification and subgroup of CRCs, inferring a poor patient survival treatment of CRC. (Smeby et al., ESMO Open 2019). In multicentre studies we confirm that tumor microenvironment markers are PROJECTS key determinants for risk of relapse in early-stage CRC • Prognostic and predictive biomarkers (Dienstmann et al., Ann Oncol, 2019; Glaire et al., Brit J • Modeling tumor heterogeneity and clonal evolution Ca 2019). • Pharmacogenomics of solid tumors using patient-derived organoids (PDO) Much effort is put into the pharmacogenomics project: • E3 ubiquitin ligases in intercellular communication multiple ex vivo cultures from CRC liver metastases and carcinogenesis have been successful established as PDOs, and screened for sensitivity to 40 anticancer agents. Intra-patient RECENT ACHIEVEMENTS inter-metastatic pharmacological heterogeneity is In 2019 we published 20 papers, including in Ann Oncol not pronounced and variation in drug sensitivities is (2), Oncogene (2), PNAS, and Nature Rev Clin Oncol. Kaja reflected at the transcriptomic level, suggesting great Christine Graue Berg defended her PhD at the Faculty potential to develop gene expression-based predictive of Medicine, U of Oslo. Two early career scientists were signatures to guide experimental therapies (paper in rewarded for their excellence, Anita Sveen received revision). A protocol for a clinical trial implementing “Early Career Award” from OUH, and a major grant from such personalized pharmacological models is currently the Norwegian Cancer Society; Peter W. Eide received in development. the “Young researcher award” from Onkologisk Forum (Annual National Oncology meeting).

42 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Epigenetics Group leader: Guro E. Lind

“Epigenomics – reversible changes in cancer and a source for clinical biomarkers”

ABOUT RECENT ACHIEVEMENTS Molecular OncologyIn the group of Epigenetics we are studying DNA During 2019, the group has continued the development methylation alterations by integrating genome wide of a urine-based test for monitoring of bladder cancer methylation profiling (sequencing and arrays), with patients. A set of biomarkers, identified in-house using detailed candidate gene characterization. The research methylome sequencing, demonstrated high accuracy in is performed across cancer types, with a main focus on a test series and was recently validated using a blinded gastrointestinal and urological cancer. In 2019 the group prospective international patient series (manuscript). A counted eleven members: 3 postdocs/scientists, 2 PhD cohort of 50 post-surgery individuals is being followed students, 3 engineers, one study nurse, one MSc student at Aker for two years, in order to compare the urine test and the group leader, and includes a project group. to the current gold standard method (cystoscopy). Full follow up time will be reached in 2020. Preliminary data AIMS indicate that the urine test enables earlier detection of 1) To identify and develop epigenetic biomarkers with bladder cancer recurrence. clinical impact, including markers for early detection and monitoring of cancer. The data have laid the foundations of a national multi- 2) To explore the inter- and intra-tumor diversity of center study aiming at demonstrating the clinical utility epigenetic aberrations in cancer, and effect on patient of the urine test. Hospitals from all health regions are outcome. participating, and the first patient was recruited in December. All together 500 patients will be followed for PROJECTS a two-year period. The study is funded through “klinisk • Epigenetic subclassification and prognostic markers behandlingsforskning” and received additional funding for colorectal cancer from the Research council in 2019. • Methylome-based early detection and monitoring of bladder and gastrointestinal cancer In 2019 Marine Jeanmougin was appointed leader of a • Epigenetic heterogeneity in gastrointestinal cancers project group with expertise in biostatistics. One PhD degree (Heidi Pharo) and one MSc degree (Ida Marie Børresen) were completed from the group in 2019.

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 43 Department of Molecular Oncology Genome Biology Group leader: Rolf I. Skotheim

“Molecular heterogeneity of prostate cancer - MolecularImproved precision diagnostics” Oncology

ABOUT prostate cancer was reported (Løvf et al., Eur. Urol, The research group studies how genomes and 2019). Here, whole-exome sequencing of 89 tumor transcriptomes are altered in cancer cells by using both foci from 41 patients revealed that different tumor foci computational and wet-lab based approaches. Mutation within the same patient only exceptionally share any analyses in cancer benefit from knowing which genes somatic mutations. A follow-up study pointed out that and variants that are expressed, and the group has existing molecular signatures are useless in the clinic if specialized in RNA-level analyses. Further, most projects inter-focal heterogeneity is not considered (Carm et al., focus on prostate cancer. An interdisciplinary set of Sci. Rep., 2019). This is important for how genetics can expertise is beneficial for genome-scale cancer research, inform on treatment decisions as information from all and the personnel have their education across the tumor foci is necessary to conclude about the cancer. disciplines biology, informatics, and medicine. Through The group continued to develop bioinformatics pipelines 2019, the group consisted of twelve members. for high-throughput sequencing of DNA and RNA. A paper in press describes a tool for sensitive fusion gene AIM detection and with biomedical data from testicular To improve the diagnosis and management of cancer by cancer (Zhao et al., NAR Genomics and Bioinformatics). utilizing genome technologies. In addition to these three articles, the group contributed to four publications from internal and external PROJECTS collaborations. • Interfocal heterogeneity of prostate cancer • RNA variation caused by aberrant splicing and as a In 2019, three MSc degrees were achieved. Karina source of cancer biomarkers Borlaug got her degree at Dept. Informatics, whereas • Fusion gene identification and characterization Susanne Kidd and Linn Olsen got theirs from Dept. Molecular Biosciences. RECENT ACHIEVEMENTS During 2019, the group continued the development of a Important research funding was obtained from the large prostate cancer research program. The first large Norwegian Cancer Society and South-Eastern Norway in-depth genomic heterogeneity analysis of primary Regional Health Authority.

44 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Molecular Oncology

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 45 “Our goal is to develop new Radiationpredictive methods Biology and treatment strategies for improved radiation therapy” Department of Radiation Biology Headed by Kristian Berg

The Department has more than 60 employees organized KEY ACHIEVEMENTS THE LAST 3-4 YEARS INCLUDE in 4 research groups and 6 project groups. The research • Pancreatic carcinoma xenografts treated with sunitinib at the department is focused on the biological responses show less abnormal microvessels but larger hypoxic to ionizing and non-ionizing radiation, including regions after treatment than before treatment; γ-radiation, radiation from radionuclides, ultraviolet • Cervical cancer patients with tumors showing high radiation, visible light as well as proton therapy. hypoxic fraction in combination with high interstitial Our department is actively engaged in revealing fluid pressure have particularly poor prognosis with a the mechanisms involved in DNA repair, cell-cycle 5-year survival rate of only 13 %; regulation, genomic instability and immune responses • A novel mechanism of activation of the DNA damage after radiation, the impact of hypoxia on the radiation kinase;ATR (Ataxia Telangiectasia and Rad3-related) response and predictive markers for the outcome of was identified; radiotherapy of cancer patients. The department is also • PCI has been found to efficiently enhance antigen pres- involved in delivering radionuclides to cancer tissue. entation during anti-cancer vaccination.; Another research area is the use of visible light to • A production unit for biomolecular therapeutics has Radiation Biologyactivate photosensitive compounds, thereby generating been established. Several new recombinant targeted reactive oxygen species, which are used for cancer protein toxins have been developed and are under detection and therapy. In that respect a technology has preclinical evaluation; been developed, photochemical internalization (PCI), • Documented for the first time that protons can activate which enables site-directed intracellular delivery of photosensitizers used in photodynamic therapy (PDT) anticancer therapeutics. to mimic responses as in PDT; • A new method to image hypoxia in prostate cancer OUR GOALS ARE based on integration of images reflecting oxygen con- • To understand the molecular and physiological mech- sumption and supply has been developed; anisms behind tumour response to radiation, and to • We gained important new knowledge about the regula- develop predictive methods and treatment strategies; tion of translation in response to cellular stress as well • To utilize acquired knowledge to establish new radiation- as about the function of the stress-response kinase based treatment regimens with improved specificity GCN2 in human cells; and efficacy towards cancer cells; • Combinatorial drug partners were identified that over- • To develop treatment strategies utilizing non-ionizing come resistance to CD37-targeted radioimmunothera- radiation combined with photosensitizing agents, py in B cell lymphoma; either to induce tumour cell kill directly or via • Described a key mechanism required for formation of internalization of therapeutic or sensitizing agents. Hh-signaling competent cilia that is potentially exploit- able as treatment target for Hh-dependent cancers.

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 47 Department of Radiation Biology Photochemical Internalization Group leader: Kristian Berg

“Our goal is to develop and optimize the PCI technology for treatment of solid cancers”

ABOUT PROJECTS Group members: 21, including 5 researchers, 5 postdocs, • Design and development of recombinant 3 PhD students, 6 technical positions and 2 MSc immunotoxins for activation by PCI students, including the project groups of Asta Juzeniene, • Light-controlled delivery of cancer Pål Kristian Selbo, Anette Weyergang and Theodossis immunotherapeutics including PCI of 1) immunotoxins RadiationTheodossiou. targeting cancer stem cells (CSCs) and 2) CSC-derived Biology vaccines. Project Photochemical Internalization (group leader • Utilize new vehicles for targeted delivery of small Berg, project leaders Selbo, Weyergang and Theodossiou): molecular drugs to endocytic vesicles for activation by Endocytic entrapment is a hurdle for therapeutic PCI utilization of macromolecular therapeutics with • Evaluation of the vasculature as a target for PCI intracellular targets. Photochemical internalisation and further utilize these effects to reach a curative (PCI) is a technology for cytosolic release of therapeutic endpoint macromolecules subjected to endocytosis. PCI is invented • Using mitochondria-powered chemiluminescence to and developed in our research group and is currently non-invasively treat inaccessible tumours evaluated in clinical trials. • Utilizing other radiation sources to induce PCI effects • Targeted alpha radionuclide therapy for bone and Project Targeted alpha therapy (project leader Juzeniene): visceral metastases of osteosarcoma, prostate and Metastases are the primary cause of death in cancer breast cancer patients. Targeted alpha-particle therapy is a promising treatment for eradicating micrometastases. RECENT ACHIEVEMENTS • Documented for the first time that protons can AIMS activate photosensitizers used in photodynamic Project Photochemical internalization: therapy (PDT) to mimic responses as in PDT;Published The main aim of our group is to develop and optimize in Nature Comm. the PCI technology for treatment of solid cancers with a • The new FET-OPEN project FRINGE (Co-ordinator: curative endpoint. Theodossiou) was launched in 2019, • New grants in 2019: PhD stipend from HSE (Selbo); Project Radionuclide therapy: Project grant from Radforsk (Weyergang) The main goal is to develop a novel technology with • Theodossis A. Theodossiou awarded the prize potentially broad therapeutic applications for cancer researcher of the year at the Institute for Cancer micrometastases by means of dual targeted alpha Research particle radiation. • The EU Innovative Science 2019 awarded to the Lumiblast project (Theodossiou and Berg) • No. of papers in 2019: 8 • MSc thesis: 2

48 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Clinical Radiation Biology Group leader: Heidi Lyng

“Our goal is to discover biomarkers and molecular targets for combination therapies with radiation”

ABOUT AIMS Group members: 10, including one researcher, four • Understand molecular mechanisms behind radiore- postdocs, three PhD students, and two technicians. sistance of cervical and prostate cancer • Develop biomarkers and find drug targets for person- The focus is to develop molecular biomarkers that can alized radiotherapy of patients with these diseases Radiationidentify patients at risk of radiotherapy failureBiology and to find targets for therapeutic intervention in a combined PROJECTS radiotherapy regimen. The research projects are run in • Genetic alterations and chemo-radioresistance in close collaboration with medical doctors and physicists cervical cancer at the hospital. • Molecular hypoxia biomarkers in cervical and prostate cancer The work is based on tumor biopsies and blood samples • Combined molecular and imaging biomarkers in cervi- collected at diagnosis or during therapy. cal and prostate cancer Whole genome methodology is used, including microarray and sequencing techniques, which provides RECENT ACHIEVEMENTS new insight into the disease and enables identification In 2019, the group published 4 articles. Major findings of novel biomarkers and drug targets. We also explore were: whether functional tumor images (MRI/PET) can aid the • Discovery of a miRNA candidate biomarker for hypox- translation of the molecular findings into radiotherapy ia related treatment resistance in cervical. practice. • Identification and exploration of an aggressive cervical phenotype with elevated oxidative phosphorylation and proliferation activity.

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 49 Department of Radiation Biology Radiation Biology and Tumor Physiology Group leader: Einar K. Rofstad

“Our goal is to identify strategies for personalized Radiationradiation therapy of cancer” Biology ABOUT PROJECTS Group members: 7, including 2 researchers, 4 postdocs, 2 • Clinical and preclinical MRI of the physicochemical PhD students, and 1 technician. microenvironment of tumors • Treatment strategies targeting the physicochemical The focus of the group is to improve the outcome microenvironment of tumors of radiation therapy of cancer. Poor outcome is a consequence of radiation resistance and elevated RECENT ACHIEVEMENTS metastatic propensity of the primary tumor, and our Anette Hauge defended her Doctor Philosophiae (Dr research is based on the hypothesis that poor outcome Philos) thesis at the Faculty of Mathematics and Natural is caused primarily by an abnormal physicochemical Sciences, University of Oslo in 2019. The thesis (The tumor microenvironment. Xenografts of human cervical Tumor Microenvironment and Its Assessment with carcinoma, pancreatic carcinoma, and malignant DCE-MRI and DW-MRI) consists of 4 first-author and 3 melanoma are used as preclinical tumor models. In second-author papers. addition to standard molecular biology methods, important methods include intravital microscopy, Our group developed novel MRI methods for MRI, and probe measurements of physicochemical characterizing the physicochemical microenvironment parameters. of tumors in 2019.

AIMS Important scientific findings in 2019: To reach the primary goal, our research is divided into • Highly elevated tumor interstitial fluid pressure two arms with the following aims: is a stronger biomarker of the outcome of locally • To develop MRI-based methods that can advanced carcinoma of the uterine cervix than high provide information on the physicochemical fraction of hypoxic tumor tissue. microenvironment, metastatic propensity, and • Antiangiogenic treatment of cervical carcinoma with radiocurability of tumors bevacizumab may cause increased tumor hypoxia, • To develop treatment strategies for normalizing the owing to treatment-induced vessel pruning. physicochemical microenvironment, decreasing the metastatic propensity, and enhancing the radiocurability of tumors

50 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Radiation Biology and DNA Damage Signaling Group leader: Randi Syljuåsen

“Our goal is to obtain new knowledge about cellular responses to radiation and utilize it to improve cancer Radiationtherapy” Biology ABOUT AIMS Group members • Obtain new knowledge about cellular responses to 14.3 including 5 researchers, 1 postdoc ,5 PhD students radiation, with focus on cell cycle checkpoints, DNA and 3.3 technicians. damage signaling and repair, and explore how such knowledge can be used to improve radiotherapy. Theme In radiotherapy ionizing radiation is used to cause DNA PROJECTS damage in cancer cells. The DNA damage is rapidly • Pre-clinical exploration of the effects of checkpoint sensed and a network of intracellular DNA damage kinase (CHK1, WEE1, ATR) and PARP inhibitors signaling cascades is activated. These signaling cascades • Functional roles of Protein phosphatase 1 (PP1) influence whether the cells die or survive, through targeting subunits in DNA damage signaling regulation of DNA repair, cell cycle checkpoint and • Identification of drugs that inhibit DNA repair after cell death pathways. Our group works at the border radiation, through flow cytometry-based compound between basic and translational radiation research. We screens conduct basic projects to identify novel mechanisms • Centrosomal and ciliary proteins in cell cycle of DNA damage signaling, in addition to more applied regulation and genome integrity- roles and targets in projects to understand how inhibitors of DNA repair cancer etiology, diagnostics and treatment and checkpoints can be used in an optimized manner • The role of GCN2 and translational regulation in the for cancer treatment. Three project groups, headed by cell cycle and cellular stress Beata Grallert Trond Stokke and Sebastian Patzke, are members of our group. RECENT ACHIEVEMENTS: In 2019, a total of 10 articles were published. Members of the group were senior/first authors on 6 of these, published in Nucleic Acids Research, Cell Reports, Frontiers in Oncology, Cell Cycle, Current Genetics and Bioessays. One new grant was obtained from the Norwegian Research Council.

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 51 “Preclinical and Tumorclinical efforts Biology towards precision oncology”. Department of Tumor Biology Headed by Gunhild M. Mælandsmo

The department has four research groups and 54 multidisciplinary tumor boards in the area of precision employees with a common vision to improve treatment cancer medicine. of metastatic cancer. Our strategy is, through basic and translational research in the areas of cancer Key achievements over the last 3-4 years include: biology and computational science, to advance systems • Project leader responsibilities in collaborative projects understanding and identify novel intervention strategies. in precision cancer medicine: We emphasize multidisciplinary competence and NCGC - The Norwegian Cancer Genomics Consortium, collaboration between researchers, clinicians and NoSarc - Norwegian Sarcoma Consortium, MetAction patients to stimulate the necessary synergy for improved - Actionable targets in cancer metastasis, MOVEMBER cancer care. - The Norwegian Prostate Cancer Biomarker Consortium, The EuroPMP Cost Action, Biobank We are performing basic, translational and clinical Norway 2 – multicenter biobanking of prostate cancer Tumor Biologyresearch, and our scientific goal is to provide knowledge tissue in Norway for clinical translation of precision cancer medicine. We • Project leader responsibilities for clinical trials: will do so by contributing with expertise in genomics NeoAva: Bevacizumab in combination with and bioinformatics and by utilizing patient samples as neoadjuvant chemotherapy in breast cancer model systems for investigation of therapeutic efficacy. I-BCT: DNA targeted chemotherapy to breast cancer We have a large collection of patient-derived cell lines patients with an aggressive phenotype and xenografts from different types of human cancer. ImmunoPeCa: Immunotoxin in Peritoneal The models are utilized for mechanistic studies of disease Carcinomatosis progression and treatment responses, and for preclinical • Co-PI responsibilities in the METIMMOX multicenter evaluation of novel drugs and drug combinations. trial which will investigate the combination of oxalip- Together with patient samples, collected in consecutive, latin and checkpoint inhibition (nivolumab) in micro- longitudinal or study-specific biobanks, the patient- satellite stable metastatic CRC derived models serve as resources to identify novel targets and biomarkers. • All research groups have during the period received major funding (Norwegian Cancer Society, H2020, To foster a strong link between translational and clinical South-Eastern Norway Regional Health Authority) research we have several researchers holding part-time • The department has published 66 papers, with 28 as clinical positions. An ambition for the department is to first or last author, and educated three PhDs and one participate in design and conduct of clinical trials, and M.Sc. in 2019 to provide molecular and bioinformatics competences in

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 53 Department of Tumor Biology Metastasis Biology and Experimental Therapeutics Group leader: Gunhild M. Mælandsmo

“Cellular plasticity - the route to resistance and metastasis”

ABOUT 2. Preclinical research investigating novel drugs and Employees: The group has 20 members with drug combinations multidisciplinary background and expertise (cell- and • Mechanistic studies and assessment of treatment molecular biologists, medical doctors, laboratory- and efficacy in patient-derived models in vivo and ex Tumoranimal technicians), including two MDs in shared vivo Biology clinical positions. Several of the technicians are trained • Biomarker discovery by molecular and functional in specialized technologies and compose resources for all techniques groups in the department. • Response evaluation of experimental drugs (often in collaboration with commercial partners, eg.: Research focus: Investigations on mechanisms of Lytix Biopharma and Arctic Pharma) resistance and metastasis for improved cancer 3. Clinical trials in precision medicine – clinical and treatment. translational efforts towards biomarker discovery • NeoAva: bevacizumab in combination with Methodology: Molecular and functional analyses neoadjuvant chemotherapy for patients with locally utilizing clinical samples, human cell cultures and advanced breast cancer patient-derived models (ex vivo, in vitro and in vivo). • I-BCT: extended DNA-targeted chemotherapy to breast cancer patients with an aggressive AIMS phenotype Metastatic progression is the major clinical challenge and the principal cause of death in cancer patients. To RECENT ACHIEVEMENTS combat metastatic cancer our goal is to understand • The group was credited with 20 publications in 2019, the underlying biological mechanisms causing therapy of which nine with group members as first and/or last resistance, invasion and re-growth. Knowledge on these author; two PhD degrees completed processes is vital for identification of molecules that can • One clinical intervention trial in breast cancer open be utilized as prognostic and predictive biomarkers or for inclusion (I-BCT) as targets for therapy. We are working with malignant • Successful establishment of a user board for melanoma, breast cancer and prostate cancer. melanoma research • Funding: Two innovation grants from the South- PROJECTS Eastern Norway Regional Health Authority, one 1. Basic research revealing mechanisms causing researcher grant for biomarker stratification in breast treatment resistance and metastasis cancer and two partnerships in new H2020-projects • Molecular and cellular determinants regulating • One patent approved cancer cells plasticity, with special emphasis on the role of tumor-stroma interactions

54 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Translational Cancer Therapy Group leader: Kjersti Flatmark

“Cellular plasticity - the route to resistance and metastasis” “New treatment for metastatic colorectal cancer”

ABOUT PROJECTS In 2019, the Translational Cancer Therapy group • Peritoneal metastasis – molecular targets and new comprised 16 members (including part-time employees therapies and students) with a broad variety of expertise, - Personalizing CRC therapy – identification of Tumor Biologyincluding basic biologists, translational scientists, biomarkers and therapeutic targets in locally and clinician-scientists. Our approach to research is advanced and metastatic CRC, involving generation translational, encompassing methods from biochemistry and use of our extensive biobanks, molecular and cell biology, preclinical drug testing in animal and bioinformatics analyses (subprojects include: models, biomarker studies in clinical cohorts and genomics, microRNA, mRNA, and immune cell interventional clinical trials. Extensive collaboration analysis, participation in the BigMed project) has been established within the Institute, with clinical - Novel drugs and therapeutic concepts in models of departments, nationally and internationally. peritoneal and liver metastases • Translational studies within the METIMMOX AIMS multicenter trial (Colorectal Cancer Metastasis – Our long-term aim is to make new, efficacious Shaping Anti-Tumor Immunity by Oxaliplatin), which treatment(s) available to patients with colorectal will investigate the combination of oxaliplatin and cancer (CRC). This will be accomplished by bringing checkpoint inhibition (nivolumab) in microsatellite the clinic and lab together in translational research stable CRC projects utilizing 1) preclinical models for efficacy • Commercial development of MOC31PE and BM7PE and mechanistic studies 2) clinical cohort studies to immunotoxins for cancer therapy understand CRC biology and identify biomarkers and therapeutic targets 3) clinical intervention trials to test RECENT ACHIEVEMENTS new drugs and therapeutic concepts in patients. • Group members were credited with 25 publications in 2019 • The multicenter METIMMOX trial has included almost half of the planned number of patients, and interesting responses have been registered • Our COST Action, EuroPMP, European Research Network on rare cancer pseudomyxoma peritonei currently comprises >80 members from 21 European countries. • Two patent applications filed

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 55 Department of Tumor Biology Computational Cancer Genomics Group leader: Eivind Hovig

“Enabling the transition to clinical utility”

ABOUT PROJECTS TumorThe 10-member group has strong interest in the • Development of solutions for integrative cancer Biology development of computational approaches in cancer sequencing towards diagnostic utility, for patient genomics, with focus on melanoma systems biology, and stratification, and prediction of treatment response prostate cancer functional genomics. Further activity is • Participation in national and international efforts for centered on computational aspects of deep sequencing standardization and development of best practice for cancer, with downstream analysis. The group methods, including the 1 Million genomes community facilitates moving precision cancer medicine towards effort, partner of the BigMed project, and participating the clinic, leveraging participation in the BigMed RCN- in the Center of innovation Big Insight for the financed ICT lighthouse project. knowledge economy. • Melanoma signaling perturbations for systems The group collaborates with deCODE, Iceland, on the understanding, including MITF, BRAF and CDKN2A characterization of a familial cancer biobank, with 16000 aberrations genotyped samples, and where 2000 Norwegians have • Biomarkers in prostate cancer epigenomics been whole genome sequenced. We pursue both the • Identification of familial cancer predisposing variants heritable cancer information from this effort, as well as in Norwegian families with overrepresentation of a characterization of the ethnic Norwegian population cancer genetics as a communal resource for Norway. • Clinical implications of Lynch syndrome genetics in Europe and Latin America AIMS • to develop and apply novel methodologies for RECENT ACHIEVEMENTS computational studies of cancer-related processes, • Group members were credited with 15 publications in including statistical genomics, drug prediction 2019, with 8 as first or last author algorithms, and mutational processes • Cancer society research funding for prostate cancer to • to contribute insight on heritable cancer-predisposing Alfonso Urbanucci DNA-variation in the Norwegian population • to characterize geographical stratification aspects of the Norwegian population • to develop solutions for precision cancer medicine towards the clinic • to understand signaling and epigenetic processes in melanoma and prostate cancer

56 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Molecular Biology of Sarcomas Group leader: Jørgen Wesche

“Towards precision medicine to improve treatment of sarcomas”

ABOUT PROJECTS Tumor BiologyThe 14-member group has a long standing interest in the • Sarcoma cell biology – Gaining understanding of the biology of mesenchymal tumors (sarcomas). The current development and progression of rhabdomyosarcoma, focus is on precision medicine for sarcomas. To achieve liposarcoma and osteosarcoma, which will lead to the this, the group has broad expertise in basic cell biology, identification of biomarkers and novel drug targets. A genomics and translational research and, in addition, main focus is the study of the role of fibroblast growth one MD in a shared clinical position. The group is part of fact receptors (FGFRs). a Centre of Excellence (CanCell). • Norwegian Sarcoma Consortium (NoSarC) – Biobanking and genomic characterization of patient AIMS material of 3-4 national cohorts of sarcomas (~500 The group aims to improve the treatment of sarcoma samples). patients by investigating how genetic changes • Exploration of “liquid biopsies”, as a non-invasive (mutations) affect signalling in sarcoma cells, and methods for detection of tumor-derived DNA in blood, how tumors evolve and become resistant. We combine to monitor disease progression, treatment response extensive genomic characterization of clinical cohorts and tumor evolution. with preclinical investigation in sarcoma cell lines and • Dissecting drug resistance in gastrointestinal stromal xenografts to better understand the biology of sarcomas. tumors - Revealing the underlying mechanisms of Sarcomas are rare cancers with poor treatment options, early drug resistance in light of the complexity of the and we aim to use our biological knowledge to identify tumor to identify novel treatment modalities. new treatments opportunities by repurposing approved drugs for other cancers types. RECENT ACHIEVEMENTS • 10 publications in 2019 • The group obtained a grant from the South-Eastern Norway Regional Health Authority (PhD project). • Group visit to Vall d’Hebron, Barcelona, resulted in a new important collaboration • 1 Master degree was completed

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 57 “Providing cutting- edge technology and competence Coreto excel research” Facilities Department of Core Facilities Headed by Leonardo A. Meza-Zepeda

The Department of Core Facilities runs six regional cooperates with nodes at the Rikshospitalet and Ullevål and national technology platforms financed by the campuses of OUH, as well as the light microscopy core South-Eastern Norway Regional Health Authority and facility at the Institute for Biosciences, University of the Research Council of Norway, providing advanced Oslo. The core facility for ALM is a Eurobioimaging competence, infrastructure, and services to regional, node, providing state-of-the-art technologies in the national and international users. The Department fields of biological and medical imaging. Services include aims to deliver easy access to cutting-edge advanced training, courses, access to microscopes and microscopy technologies and competence, and to improve research performed by competent core facility personnel. Core Facilitiesquality through an optimal choice of technology, ultimately increasing the scientific competitiveness of ADVANCED ELECTRON MICROSCOPY our users. The Department of Core Facilities is organized Unit Leader: Ellen Skarpen in three units; Advanced Microscopy, Genomics and Scientifically responsible: Andreas Brech Bioinformatics, and Flow Cytometry and Pre-Clinical Facility staff: 1 Imaging, with a total of 20 employees. More information The Core Facility for Advanced Electron Microscopy at www.ous- research.no/corefacilities. (AEM) includes nodes at the Radium Hospital and Rikshospitalet, and provides service, training, and access ADVANCED LIGHT MICROSCOPY to microscopes for ultrastructural studies. Available Unit Leader: Ellen Skarpen techniques at the facility include conventional plastic Scientifically responsible: Harald Stenmark embedding, immune EM, correlative light/electron Facility staff: 2 microscopy (CLEM), high-pressure freezing, electron The Core Facility for Advanced Light Microscopy (ALM) tomography, cryo-EM and STEM. The facility staff is offers services in various types of ALM, including actively developing new methods in order to offer state- confocal microscopy, live-cell microscopy and of-the-art microscopy solutions for researchers. superresolution microscopy. Current instruments include We cooperate with the imaging platform at the Institute a Zeiss LSM 880 FAST airyscan microscope, a Zeiss LSM for Biosciences, University of Oslo and are part of the 710 confocal microscope, and an OMX Blaze microscope Norwegian Advanced Light Microscopy node within for structured illumination and STORM super-resolution EuroBioImaging. imaging, as well as live-cell microscopy. The core facility

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 59 Department of Core Facilities

BIOINFORMATICS FLOW CYTOMETRY Unit Leader: Susanne Lorenz Unit Leader: Trond Stokke Scientifically responsible: Eivind Hovig Scientifically responsible: Trond Stokke Facility staff: 5 Facility staff: 4 The Bioinformatics Core Facility (BCF) provides service, The Flow Cytometry Core Facility (FCCF) provides support and advice in the field of bioinformatics. By analysis and sorting services for users within the South- combining biology with computer science, statistics and Eastern Health Region of Norway. We have recently mathematical modelling, we offer support for analysis installed a state-of-the-art analyser (BD Symphony) and interpretation of biological data for basic and with 5 lasers that may measure up to 28 fluorescence translational research. parameters simultaneously. In total, the core facility The BCF has a specific focus on developing and providing provides services using 3 analysers and two sorting solutions for precision medicine and cancer-related instruments. Flow cytometry analysis is performed by Coreprojects. Through dedicated support from the South- the users themselves. Sorting experimentsFacilities are either Eastern Norway Regional Health Authority, we are performed by core facility personnel (in the BD Aria), actively assisting in developing the infrastructure for or by the users in the Sony SH100 sorter. The FCCF has precision diagnostics at the hospital. Our service possibilities for high throughput screening, processing also includes support with data handling and storage and staining of cells in 96- or 384-well plates, followed by providing approved solutions for sensitive data. The by an automated analysis. We also have a “mass-spec operation of the BCF is aligned with the national and flow cytometer” (Helios). This instrument can measure local Elixir bioinformatics infrastructure project, and also up to 60 parameters simultaneously at single-cell interacts with USIT, University of Oslo. resolution. We have recently installed an add-on to the Helios, Hyperion, which allows for imaging of sections HIGH-THROUGHPUT SEQUENCING (GENOMICS) labelled with up to 60 heavy metal-tagged antibodies. Unit Leader: Susanne Lorenz The FCCF collaborates with facility nodes at the Scientifically responsible: Leonardo A. Meza-Zepeda Rikshospitalet and Ullevål campuses of OUH. Facility staff: 5 The Genomics Core Facility (GCF) provides state-of-the- PRECLINICAL IMAGING FACILITY art high-throughput genomic services to the scientific Unit Leader: Trond Stokke community. The GCF offers advanced technologies and Scientifically responsible: Tord Hompland competence to study genome structure, dynamics and Facility staff: 2 function using high-throughput sequencing, nanoString, The Preclinical Imaging Facility provides access to state- and microarray technologies. Our services include of-the-art non-invasive imaging equipment for mice solutions to study the transcriptome, genome, and and rats. The equipment is situated within the animal epigenome from multi-gene analysis to a genome-wide facility and consists of a 7T Bruker MRI, IVIS spectrum level. Highly experienced service personnel provide and Zeiss Stereo Macroscope for optical imaging, and a advanced support to clinical, translational and basic Multirad 225 small animal irradiator capable of doing research projects. We have extended our services for x-ray imaging. The facility also provides all the necessary single-cell transcriptome analysis to the single-cell equipment for in vivo research on small animals or analysis of T & B cell receptors, scATAC-Seq, and feature tissue/organ samples from larger animals or humans. barcoding to study protein expression. In addition, we A comprehensive library of standard off-the-shelf have established a collaboration with the Department imaging protocols are available, and custom-protocols of Pathology at OUH to develop the infrastructure for can be developed upon user request. We are at present advanced precision diagnostics towards clinical studies developing a protocol for synchronization of images with dedicated support from the South-Eastern Norway obtained by MRI, IVIS and X-ray imaging. The service Regional Health Authority. The GCF is a member of the offered by the core facility includes design, development Norwegian Consortium for Sequencing and Personalised and running of the imaging experiment, as well as Medicine (NorSeq) running the National platform for post-processing of the data in addition to instrument- sequencing technology. The core facility collaborates specific training. The core facility collaborates with the with the sequencing node at the Ullevål campus for Preclinical MRI node at the Ullevål campus. sequencing services.

60 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Core Facilities

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 61 Research centres

Centre of Excellence ResearchThe Centres of Excellence (CoE) scheme is a national programme under the centres auspices of the Research Council of Norway. The granted CoE (CanCell) is funded for 5 + 5 years (if recommended following a mid-term evaluation). 64 The total basic funding is ~167 million NOK.

62 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 K. G. Jebsen Centres Research centresThe K.G.Jebsen Foundation supports Centres for Medical Research of high international quality as part of its program for translational medicine. The centres are selected in collaboration with the Norwegian Medical Faculties and University Hospitals for a period of 4 years with the possibility of a 2-year extension. The selected Centres receive 16-18 million NOK in 66 basic funding over the first four years from the Foundation and support from the host institutions, University of Oslo (KG Jebsen Centre for Cancer Immunotherapy, KG Jebsen Centre for B Cell Malignancies) or Oslo University Hospital (KG Jebsen Colorectal Cancer Research Centre).

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 63 “Reprogramming of cancer”

Centre for Cancer Cell Reprogramming (CanCell) Headed by Harald Stenmark

64 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 ABOUT Centre for Cancer Cell Reprogramming (CanCell) is a • Demonstration that Centralspindlin recruits ALIX to Norwegian Centre of Excellence (CoE) which opened the midbody during cytokinetic abscission in fruit flies 01.01.2018 and has a planned CoE funding period of 10 via a mechanism analogous to virus budding (Lie- years. CanCell is led by Harald Stenmark at Institute for Jensen et al., Current Biology, 2019). Cancer Research, whereas Anne Simonsen at Institute of Basic Medical Sciences is co-director. The centre consists • Demonstration that desumoylation of RNA Polymerase of 6 research groups and has 7 associate members III lies at the core of the Sumo stress response (Nguéa (Eivind Hovig, Åslaug Helland, Yngvar Fløisand, Philippe et al., Journal of Biological Chemistry, 2019). Collas, Arnoldo Frigessi, Emmet McCormack, and Terje Johansen) and 4 international visiting professors • Demonstration that cancer mutations in fibroblast (Kristian Helin, Ivan Dikic, Eileen White, and Eyal growth factor receptor 2 prevent a negative feedback Gottlieb). By the end of 2019, CanCell had 100 members loop mediated by the ERK1/2 pathway (Szybowska et of 34 (!) nationalities. al., Cells, 2019).

• CanCell scientists published 41 papers in 2019, many AIMS of these in leading journals. Two PhD students, Marte CanCell’s vision is to identify novel vulnerabilities Sneeggen and Ignacio Cuervo, successfully defended of cancer cells that can be targeted for cancer cell their theses. Eight MSc students were graduated. reprogramming. The centre’s founding hypothesis is that pathway intersections between chromatin regulation, • In 2019, major grants were obtained by Jorrit Enserink, membrane dynamics, cell signaling and metabolism Leonardo Meza-Zepeda, Anne Simonsen, Harald during cancer progression represent potential “Achilles’ Stenmark, Kay O. Schink, Swarupa Panda, Helene heels” of cancer cells. These will be identified through Knævelsrud and Viola Nähse. Two of these were close cooperations between specialists within these four international grants – EMBO long-term fellowship cellular processes, and will be targeted by genetic and to Swarupa Panda and Horizon-2020 Initial Training pharmacological regimens to achieve reprogramming of Network grant to Anne Simonsen. cancer cells into harmless (or dying) cells.

PROJECTS: GROUP LEADERS/STEERING COMMITTEE • Membrane dynamics in cancer • Autophagy in immunity and cancer CanCell was established by the following 6 group leaders, • Molecular medicine of leukemia who also serve as CanCell´s steering committee: • Tumour-host interactions • Molecular biology of sarcomas Harald Stenmark, Institute for Cancer Research, OUS, • Mechanisms of epigenetic regulation in cancer and Institute of Clinical Medicine, UiO

Anne Simonsen, Institute of Basic Medical Sciences, UiO, RECENT ACHIEVEMENTS and Institute for Cancer Research, OUS • Demonstration of distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in Jorrit Enserink, Institute for Cancer Research, OUS, and autophagy-related processes (Lystad et al., Nature Cell Department of Biosciences, UiO Biology, 2019). Ragnhild Eskeland, Institute of Basic Medical Sciences, • Identification of NIPSNAP proteins as “eat-me” signals UiO for autophagic degradation of damaged mitochondria (Abudu et al., Developmental Cell, 2019). This was a Tor Erik Rusten, Institute of Clinical Medicine, UiO, and collaboration between Anne Simonsen’s group and the Institute for Cancer Research, OUS group of CanCell associate member Terje Johansen. Jørgen Wesche, Institute for Cancer Research, OUS, and • Demonstration that ESCRT proteins seal the Institute of Basic Medical Sciences, UiO autophagosome during starvation-induced autophagy and autophagy of damaged mitochondria (Zhen et al., Autophagy, 2019). This was a collaboration between the CanCell groups of Harald Stenmark and Anne Simonsen.

• Identification of a new mechanism of tumour suppression – intracellular retention of matrix metalloproteinases (Sneeggen et al., Nature Communications, 2019).

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 65 “Our goal is to develop new therapeutic strategies that overcome immune tolerance to target cancer”

K.g. Jebsen colorectal cancer research centre

K.G. Jebsen Center for Cancer Immunotherapy Headed by Johanna Olweus

66 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 ABOUT in Norway using an in-house generated immune In the K.G. Jebsen Center for Cancer Immunotherapy receptor (JCIT TCR) for cancer immunotherapy. (JCIT) hosted by the University of Oslo, five Norwegian • Recruited first 300 patients to the ASAC trial that and one Dutch research group have come together to examines the effect of reversing prostaglandin E2- find new immunotherapeutic strategies that overcome mediated inhibition of tumor immunity in patients the major challenge of self-tolerance in cancer. JCIT with metastatic colorectal cancer by the end of 2019 was granted prolongation following the first 4-year (www.asac.no). period, throughout 2019. The partnering groups of JCIT • Malmberg completed a research sabbatical at UCSD span complementary competencies ranging from basic resulting in new collaborative efforts with leading proteomics, cell signaling and T-cell receptor engineering iPSC-NK/T cell environments, including Kaufman Lab to expertise in experimental clinical immunotherapy at UCSD, and Sadelain Lab at MSKCC (Sætersmoen et al, trials. This places the center in a unique position Seminars in Immunopathology 2019, Hong et al., Journal of to pursue novel therapeutic opportunities, and the Clinical Investigation in press). strong focus on translating therapeutic opportunities • Demonstrated that idelalisib preferentially inhibits is a fundamental characteristic of JCIT. Results from human regulatory T cells, enhancing anti-tumor basic research are pursued through the necessary immunity (Chelappa et al, J Immunol., 2019) and translational steps to testing in patients, and in-depth characterized the CD28 and CD2 interactomes in mechanistic studies of patient material obtained in T cells (Skånland and Taskén, J. Immunol. 2019) experimental clinical trials are performed with the aim • Characterized how metabolic regulation through the of improved designs of immunotherapeutic strategies. FoxK1/2 master switch affects T cell function (Sukonina et al, Nature, 2019) and contributed to understanding AIMS TLR8 signaling in T cells (Meås et al., Nature Commun., in Three principally distinct approaches are pursued in press 2020). an interdisciplinary and translational program: 1. Use • Obtained funding for proteomics infrastructure of T-cell and NK-cell based alloreactivity to overcome from The Norwegian Research Council (total 50M self-tolerance. 2. Identification and targeting of cancer- NOK, Lund-Johansen partner in NAPI consortium) specific neo-antigens. 3. Enhancement of effector T-cell and funding from the Norwegian Cancer Society for function by counteracting inhibitory mechanisms. identification of HLA_bound peptides from tumor- associated antigens. PROJECTS • Obtained funding from UiO for production of • Epitope discovery to identify targets for antibodies to peptides in the ImmunoLingo immunotherapy convergence consortium (total 11.5 mill NOK, Lund- • Identify immune cells expressing immune receptors Johansen partner). that recognize and kill cells that express the identified targets HOME PAGE • Molecular cloning, genetic transfer and profiling of http://www.med.uio.no/klinmed/english/research/ immune receptors centres/kgj-cancer-immunotherapy/ • Enhance cytotoxic lymphocyte function by overcoming inhibitory mechanisms GROUP LEADERS/ STEERING COMMITTEE • In vivo evaluation of immune modulating therapies Johanna Olweus (MD, PhD, Director), Dept of Cancer Immunology, Institute for Cancer Research, Oslo RECENT ACHIEVEMENTS University Hospital (OUH)-Radiumhospitalet and • Deciphered molecular mechanisms of NK cell University of Oslo (UiO) homeostasis, education and differentiation (Goodridge et al, Nature Communications, 2019, Jacobs et al., J. Karl-Johan Malmberg (MD, PhD, deputy Director), Dept Immunology 2019 and Pfefferle et al., Cell Reports 2019). of Cancer Immunology, Institute for Cancer Research, • Described a technology for identification of OUH-Radiumhospitalet and UiO neoantigen specific T cells from healthy donors (Ali et al, Nature Protocols, 2019) Arne Kolstad (MD, PhD), Dept of Oncology, OUH- • Olweus was awarded an ERC Consolidator Grant Radiumhospitalet (2 mill Euro over 5 yrs) for an application based on results generated within the center – “Outsourcing Kjetil Taskén (MD, PhD), Dept of Cancer Immunology, cancer immunity”. Institute for Cancer Research, OUH-Radiumhospitalet • Reported low and variable tumor reactivity of the and UiO intratumoral TCR repertoire in human cancers (Scheper et al, Nat. Med. 2019) Fridtjof Lund-Johansen (MD, PhD), Dept of Immunology, • Included 10 patients in Lymvac-2, an experimental OUH-Rikshospitalet immunotherapy trial combining intratumoral immunotherapy with anti-PD1 for treatment of Ton Schumacher (PhD), The Netherlands Cancer patients with follicular lymphoma, in collaboration Institute, Amsterdam with Merck (Kolstad PI). • Started GMP virus production for first clinical trial

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 67 “From basic research and preclinical studies to precision medicine for B-cell malignancies”

K.g. Jebsen colorectal cancer research centre

K.G. Jebsen Centre for B-cell malignancies Headed by Ludvig A. Munthe and June H. Myklebust

68 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 ABOUT • Investigated inheritance of susceptibility to malignant The K.G. Jebsen Centre for B-cell malignancies was blood disorders (Jønsson, Sci Rep. 2019). established in June 2018, and bridges 4 translational • Stromal cell PKC-beta inhibition enhances research groups with 3 clinical groups; placing us in chemosensitivity in B-cell malignancies and a unique position to translate pre-clinical results into overcomes drug resistance (Park, Sci Transl Med, in press clinical trials in lymphoma, B-cell leukemia and multiple 2019). myeloma (MM). The centre utilizes “cutting edge” • Developed in vitro phospho-flow cytometry assay technologies for deep profiling of patient samples, cancer for biomarker discovery and dose prediction in CLL drug sensitivity screens for precision medicine, and (Skånland, Leukemia, in press 2019). development of novel approaches for immunotherapy. • Distinct subtypes of diffuse large B-cell lymphoma can Collectively, the Centre represents a multidisciplinary be defined by hypermutated genes (Alkodsi, Leukemia integration of life science research with preclinical 2019). development of personalized medicine, drug discovery • Developed the prognostic predictor BTK-FLIPI to and cell-based immunotherapy, as well as clinical trials identify follicular lymphoma patients at high risk and establishment of best practice on how to treat B-cell for adverse disease (Steen, Haematologica 2019), and malignancies. contributed to convergence of risk prediction models (Silva, Haematologica 2019). AIMS • Identified TIGIT and PD-1 as relevant targets for co- The centre aims to identify, develop and test new checkpoint blockade in B-cell lymphoma (Josefsson, therapeutic options for patients with B-cell malignancies. Cancer Immunol Res 2019). • Identified tumor-reactive T cells in B-ALL patients PROJECTS (Bürgler, Oncogene 2019). • Identify molecular biomarkers to guide precision • Bone marrow Th1 T cells induce activation and medicine and to identify high risk patients proliferation of leukemic cells from B-ALL patients • Deciphering signal integration and interactions with (Traxel, Oncogene 2019). the tumor microenvironment to reveal actionable • Preclinical development of CD37 CAR T-cell therapy targets (Köksal, Blood Adv 2019; patent filed). • Develop novel therapeutics: identify antigens for • The PI3Kδ inhibitor idelalisib enhances anti-tumor vaccination, T-cell epitope discovery, and CAR T cell immunity preferentially through inhibition of design regulatory T cells (Chellappa, J Immunol, 2019), and CSK • Preclinical testing: immunotherapy and personalized binds CD28 upon activation and mutes downstream medicine signaling (Skånland, J Immunol 2019). • Translating results into clinical initiatives – from • B-cell receptor ligation induces display of V-region bench to bedside and back immunoglobulin peptides on MHC class II molecules to T cells (Hutszky, PNAS 2019) RECENT ACHIEVEMENTS/CLINICAL TRANSLATION • FOXK1 and FOXK2 regulate aerobic glycolysis (Sukonia, • The clinical portfolio includes 58 clinical trials at Nature 2019). different stages, majority are researcher initiated. • Enrolled most MM patients in clinical trials HOME PAGE • Ixazomib improved progression-free survival (PFS) https://www.med.uio.no/klinmed/english/research/ after autologous stem cell transplantation in MM centres/kgj-b-cell-malignancies/ (Dimopolous, Lancet 2019). • The addition of isatuximab to pomalidomide- dexamethasone or pomalidomide to bortezomib- GROUP LEADERS/STEERING COMMITTEE dexamethasone improved PFS in refractory/relapsed Ludvig A. Munthe (MD, PhD, Centre Director)1,2 MM (Attal, Lancet 2019; Richardson, Lancet Oncol 2019). June H. Myklebust (PhD, Assistant Director)2,3 • Consensus recommendations on imaging in Geir E. Tjønnfjord (MD, PhD)2,4 monoclonal plasma cell disorders (Hillengass, Lancet Harald Holte (MD, PhD)5 Oncol. 2019). Hilde Schjerven (PhD)1,6 • Phase II trial testing CD19 CAR T-cell therapy in Erlend B. Smeland (MD, PhD)2,3 Diffuse Large B-Cell Lymphoma demonstrated 52% Kjetil Taskén (MD, PhD)2,3 overall response rate (Schuster, NEJM 2019). • Chemotherapy can be reduced in aggressive Non- 1 Dept. of Immunology, Div. for Laboratory Medicine, Hodgkin’s Lymphoma with favorable prognosis Oslo University Hospital (OUH) (Poeschel, Lancet 2019) 2 Institute for Clinical Medicine, University of Oslo • Established B-cell directed therapy as treatment of- 3 Dept of Cancer Immunology, Institute for Cancer choice in chronic cold agglutinin disease (Berentsen, J Research, OUH Blood Med 2019) 4 Dept. of Haematology, 5Dept. of Oncology, Div. for • Relapse risk and loss of lifetime after modern Cancer Medicine, OUH combined modality treatment of young patients with 6 Dept. of Laboratory Medicine, University of California, Hodgkin Lymphoma (Biccler, J Clin Oncol 2019). San Francisco.

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 69 “High quality translational research to the benefit of colorectal cancer patients”

K.G. Jebsen Colorectal Cancer Research Centre Headed by Ragnhild A. Lothe

70 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 ABOUT enable testing and optimization of immunotherapy. Peter Colorectal cancer (CRC) is a major global health burden, and Wold Eide received the Young Researcher Award from the the focus of our Centre is to meet the current challenges in national annual meeting in oncology (“Onkologisk Forum”) disease management by improved patient monitoring and for his studies in CRC genomics, and Sveen received the Early stratified treatment. The Centre is hosted by the Clinic for Career Award from OUH. Heidi Pharo and Kaja Christine Cancer Medicine, Oslo University Hospital (OUH). The Centre Graue Berg defended their PhDs at the UiO. PIs are also partners in the recently appointed OUH Strategic Research Area TEAM-ACT (2019-24). 2019 was a successful year for the Centre with respect Home page: www.colorectalcancer.no to scientific production. Together with collaborator Scott Kopetz at The MD Anderson Cancer Centre, USA, a practice GROUP LEADERS/STEERING COMMITTEE changing clinical trial of targeted combination therapy • Professor Ragnhild A. Lothe (MSc, PhD, Centre leader), in metastatic CRC was published in NEJM (Kopetz et al., Dept. of Molecular Oncology, Institute for Cancer 2019), in addition to a comprehensive review on biomarker- Research, OUH and Institute for Clinical Medicine, guided therapy for CRC (Sveen et al., Nature Rev Clin Oncol University of Oslo (UiO) 2019). Totally 31 peer-reviewed papers were published • Professor Arild Nesbakken (MD, PhD, deputy Centre within a broad range of topics. Epidemiological research leader), Dept. of Gastrointestinal Surgery, OUH and demonstrated a rising incidence of CRC among young Institute for Clinical Medicine, UiO people (Araghi M et al., Lancet Gastroenterol Hepatol • Professor Rolf I. Skotheim (MSc, PhD), Dept. of 2019), and compared survival after surgery for CRC in Molecular Oncology, Institute for Cancer Research, Norway to other high-income countries (Benitez Majano OUH, and Dept. of Informatics, UiO. S et al., Lancet Oncol, 2019). Molecular studies were • Senior Consultant Marianne G. Guren (MD, PhD), published of circulating biomarkers for management of CRC Dept. of Oncology, OUH (Hamfjord J et al., Ann Oncol 2019), the strong influence • Professor Guro E. Lind (MSc, PhD), Dept. Molecular of tumor microenvironment features on patient prognosis Oncology, Institute for Cancer Research, OUH and (Dienstmann et al., Ann Oncol, 2019; Glaire et al., Brit J Ca Dept. of BioSciences, UiO 2019), tumor heterogeneity and multi-level genomics (Berg et al., Oncogene 2019; Brunsell et al., Eur J Surg Oncol; Smeby Our Centre has an active Patient Advisory Board, et al., ESMO Open 2019), as well as advanced technologies established in 2016. (Eilertsen et al., Cancer Letters 2019; Lopes et al., Lab Invest 2019). AIM Translate biomedical knowledge in the context of tumor Unpublished results of drug screening and molecular heterogeneity into improved stratified medicine of CRC. profiling of organoids derived from 30 patients with multiple CRC liver metastases, gene expression-based classification PROJECTS in a tumor heterogeneity context, and identification of new • Clinical and molecular biomarkers for improved risk high-level amplifications in CRC were recently presented stratification of patients at the Keystone Symposium on “Cancer Evolution and • Model tumor heterogeneity and clonal evolution to Combinatorial Cancer Therapies” in Banff, Canada. monitor early relapse and treatment failure • Pharmacogenomic profiling of organoid models Key opinions: derived from the patients’ own tumor cells to guide Centre members published several editorials and reviews therapy selection, identify biomarkers for response related to a variety of challenges in CRC: “The complexity prediction, and develop synergistic drug combinations of biomarkers” (Sveen et al., Nat Rev Clin Oncol); “The global challenge of CRC” (Guren MG, Lancet Gastorenterol RECENT ACHIEVEMENTS AND CLINICAL TRANSLATION Hepatol); “Gene expression-based modelling of targeted In 2019, we were granted a 6-year strategic research area therapies” (Sveen et al., Ann Oncol 2019); “Combination from OUH (TEAM-ACT) to continue the translational and therapies with HSP90 inhibitors” (Kryeziu et al., BBA Rev clinical research program on primary and metastatic CRC Cancer); “Circulation biomarkers for early detection and established in the K.G. Jebsen Centre. TEAM-ACT is led by management” (Marcuello et al., Mol Aspects of Medicine). professor R. A. Lothe and associate professor Anita Sveen. Also modelling costs and survival of several treatment Sveen also received a major grant from the Norwegian strategies of CRC was published (Joranger et al., EurJ Health Cancer Society to further develop the platform for pre- Econ). clinical pharmacogenomics of patient-derived models to

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 71 SPAIN IRELAND

FRANCE THE NETHERLANDS SPAIN IRELAND UNITED KINGDOM BELGIUM FRANCE THE NETHERLANDS GERMANY SWITZERLAND UNITED KINGDOM BELGIUM ITALY CZECH REPUBLIC InternationalGERMANY SWITZERLAND DENMARK HUNGARY ITALY CZECH REPUBLIC NORWAY CROATIA DENMARK HUNGARY SWEDEN INDIA NORWAY CROATIA CollaborationFINLAND SINGAPORE SWEDEN INDIA POLAND ISRAEL FINLAND SINGAPORE USA AUSTRIA GREECERUSSIA POLAND ISRAEL CANADA AUSTRALIA USA TUNISIA AUSTRIA GREECERUSSIA PORTUGAL ICELAND CANADA AUSTRATLIUNIA SIA SPAIN IRELAND PORTUGAL ICELAND FRANCE THE NETHERLANDS SPAIN IRELAND UNITED KINGDOM BELGIUM FRANCE THE NETHERLANDS GERMANY SWITZERLAND UNITED KINGDOM BELGIUM ITALY CZECH REPUBLIC GERMANY SWITZERLAND DENMARK HUNGARY ITALY CZECH REPUBLIC NORWAY CROATIA DENMARK HUNGARY SWEDEN INDIA NORWAY CROATIA FINLAND SINGAPORE SWEDEN INDIA POLAND ISRAEL FINLAND SINGAPORE AUSTRIA RUSSIA POLAND ISRAEL TUNISIA AUSTRIA RUSSIA

TUNISIA AUSTRALIA FINLAND HUNGARY • Garvan Institute, Sydney • Biomedicum Helsinki, University of • University of Szeged, • Kinghorn Cancer Centre, Sydney Helsinki, Helsinki Szeged • Monash University, Melbourne • Finnish Institute of Molecular Medi- cine, Nordic EMBL partner, Helsinki ICELAND AUSTRIA • Tampere University of Technology, • University of Iceland, • Medical University of Vienna, Vienna Tampere Biomedical Center, Reykjavik • Zora Oy, Espoo BELGIUM INDIA • Catholic university of Brussels, FRANCE • Indian institute of Technology, Brussels • Centre National de Génotypage, Hyderabad • Ghent University, Ghent Paris • Savitribai Phule Pune University, • Katholieke University Leuven, • EurOPDX - European Consortium Pune Leuven on Patient-derived Xenografts, Paris • Universiteit Hasselt, Genk • Institut Gustave Roussy, Paris IRELAND • Institut National de la Sante et de la • National Institute for Bioprocessing CANADA Recherche Medicale, Paris Research and Training (NIBRT), • McGill University, Montreal • Institute Cürie, Paris Dublin • Princess Margaret Hospital, Toronto • Institute of Systems and Synthetic • University of Ottawa, Ottawa Biology Genopole, UEVE, CNRS, ISRAEL InternationalÉvry • Technion - Israel Institute CROATIA • International Agency for Research of Technology, Haifa • University of Zagreb, Zagreb on Cancer (IARC), Lyon • Weizmann Institute, Rehovot • Université Lyon, Villeurbanne CZECH REPUBLIC • Université Paris-Sud, Orsay ITALY • Charles University, Prague • IFOM, Milan • Institute of Experimental Biology, GERMANY • International School for Advanced Masaryk University, Brno • EMBL, Heidelberg Studies, Trieste • Institute of Molecular Genetics, • Institut für Biochemie, University of • Istituto Nationale di Tumori, Milano Academy of Sciences of the Czech Stuttgart, Stuttgart • The Rizzoli Institute, Bologna POLAND Republic, Prague • Jacobs University, Bremen • University of Bologna, Bologna • Faculty of Biotechnology, University • National Institute of Public Health, • University of Bayreuth, Bayreuth • University of Padova, Padova of Wroclaw, Wroclaw Prague • University of Bochum, Bochum • University of Salento, Lecce • Jagiellonian University, Kraków • University of Cologne, Cologne • University of Gdansk, Gdansk DENMARK • University of Freiburg, Freiburg NORWAY • University of Heidelberg, Heidelberg • Aalborg University Hospital, Aalborg • Cancer Registry of Norway, Oslo PORTUGAL • University of Mainz, Mainz • Aarhus University Hospital, Aarhus • Haukeland University Hospital, • Institute of Molecular Pathology and • University of Marburg, Marburg • Copenhagen University Hospital, Bergen Immunology, University of Porto Copenhagen • Norwegian University of Life • Portuguese Oncology Institute, • University of Copenhagen, GREECE Sciences, Ås. Porto Copenhagen • National and Kapodistrian University • Norwegian University of Science • University of Southern Denmark, of Athens, Athens and Technology, Trondheim RUSSIA • National Centre for Scientific Odense • Stavanger University Hospital, • Institute of Cytology and Genetics, Research “Demokritos”, Athens Stavanger Novosibirsk • University of Ioannina, Ioannina • Trondheim University Hospital- St. Olavs Hospital, Trondheim SINGAPORE • University hospital of North Norway, • Cancer Science Institute of Tromsø Singapore, Singapore • University of Bergen, Bergen • University of Oslo, Oslo

72 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 SPAIN THE NETHERLANDS • University of Oxford, Oxford International• CABIMER, University of Sevilla, Sevilla • Leiden University, Leiden • Wellcome Sanger Institute, Hinxton • Centre for Biological Studies, • Netherlands Cancer Institute (NKI), Madrid Amsterdam USA • Radboud University Nijmegen, • Buck Institute for Research on • Fundacion Instituto Valenciano de • Oregon State University, Nijmegen Aging, Novato, California Oncologica (FIVO), Valencia Corvallis, Oregon • The Netherlands Proteomics Centre, • Dana Farber Cancer Institute, • ICGC, Technical validation group • Princeton University, New Jersey Utrecht Boston, Massachusetts and Ivo Gut, Barcelona • Rutgers Cancer Institute of New • University Medical Center, • Dartmouth College, Hanover, • University of Lleida, Lleida Jersey Groningen New Hampshire • University of Valencia, Valencia • Stanford University, California • VU Medical Center, Amsterdam • Duke University Medical Center, • Universitat Politècnica de València, • The Mount Sinai Hospital, New York Durham, North Carolina Valencia • The University of Kansas Hospital, • Fred Hutchinson Cancer Research • Vall d’Hebron Institute of Oncology, TUNISIA Kansas Center, Seattle, Washington Barcelona • University of Tunis, Tunis • Tisch Cancer Institute, New York • Georgetown University, Washington DC • UCSF, Helen Diller Family Cancer • Harvard University, SWEDEN UNITED KINGDOM Centre, San Francisco, California Boston, Massachusetts • Karolinska Institutet and University • Cambridge Cancer Institute, Cambridge • University of Albany, New York • Johns Hopkins Medicine, of Stockholm, Stockholm • Hampshire Hospitals/Southampton • University of California, Baltimore, Maryland • Lund University, Lund University, Southampton Berkeley, California • Lawrence Berkeley National • The Sahlgrenska Academy at • London Research Institute,The • University of Chicago, Illinois Laboratory, Berkeley, California the University of Gothenburg, Francis Crick Institute, London • University of Colorado, • Lineberger Comprehensive Cancer Gothenburg • Royal National Orthopaedic Denver, Colorado Center, Chapel Hill, North Carolina • Uppsala University Hospital, Hospital, Stanmore, Middlesex • University of Illinois, • Masonic Cancer Center and Univer- Uppsala • The Beatson Institute for Cancer Champaign, Illinois sity of Minnesota, Minneapolis Research, Glasgow • University of Washington, • Massachusetts General Hospital, SWITZERLAND • The European Bioinformatics Seattle, Washington Boston, Massachusetts • University Hospital Zurich, Zurich Institute (EMBL-EBI), Hinxton • Washington University, • MD Anderson Comprehensive • University College London Medical St Louis, Missouri Cancer Center, Houston, Texas School, UCL, London • Weill Medical College of Cornell • National Institutes of Health (NIH), • University of Cambridge, Cambridge University, New York • University of Liverpool, Liverpool Bethesda, Maryland

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 73 Recent Innovations

Registered Disclosures of Invention (DOFIs), Patent Applications and Granted Patents

Research group (inventor) Department DOFI # Karl-Johan Malmberg Cancer Immunology 19110 Kristian Berg Radiation Biology 19075 Vessela Kristensen Cancer Genetics 19074 Recent InnovationsKarl-Johan Malmberg Cancer Immunology 19055 Kjersti Flatmark Tumor Biology 19054 Therese Sørlie (Jens Henrik Norum) Cancer Genetics 19050 Kjetil Taskén Cancer Immunology 19038 Kristian Berg (Anette Weyergang) Radiation Biology 19035 June Myklebust Cancer Immunology 19021 Kjersti Flatmark Tumor Biology 19033

Application type or granted patent Research group(s) Department DOFI # Priority Application Kjetil Taskén Cancer Immunology 19038 Priority Application Kjersti Flatmark Tumor Biology 17179 PCT Application G. M. Mælandsmo, K. Flatmark, Tumor Biology, Molecular 18030 K. Sandvig Cell Biology US (National) Application Guro E. Lind Molecular Oncology 17135 US (National) Application Karl-Johan Malmberg Cancer Immunology 16132 EP (Regional) Application Karl-Johan Malmberg Cancer Immunology 16132 US (National) Application Kjersti Flatmark Tumor Biology 18153 Granted EP patent (EP 3,069,138) Johanna Olweus Cancer Immunology 13003 Granted US patent (US 10,308,980) Lothe R. A., Ågesen T.H., Sveen Molecular Oncology 11057 A., Lind G.E., Nesbakken A., Skotheim R.I. Granted EP patent (EP 2,630,261) Guro E. Lind Molecular Oncology 53212 Granted EP patent (EP 3,243,077) Kristin Austlid Taskén, Ingrid Tumor Biology 14040 15004 Jenny Guldvik Granted EP patent (EP 2,861,568) Kjetil Taskén Cancer Immunology 12047

74 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Recent Innovations

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 75 Publications

Publications 2019 Schumacher TN, Olweus J (2019) Berg KCG, Sveen A, Høland M, Al- Induction of neoantigen-reactive T agaratnam S, Berg M, Danielsen SA, cells from healthy donors Abrahamsson H, Porojnicu AC, Lind- Nesbakken A, Søreide K, Lothe RA Nat Protoc, 14 (6), 1926-1943 strøm JC, Dueland S, Flatmark K, Hole (2019) KH, Seierstad T, Moan J, Redalen KR, Gene expression profiles of Anda S, Grallert B (2019) Meltzer S, Ree AH (2019) CMS2-epithelial/canonical colorec- Cell-Cycle-Dependent Regulation High level of circulating vitamin D tal cancers are largely driven by of Translation: New Interpretations during neoadjuvant therapy may DNA copy number gains of Old Observations in Light of New lower risk of metastatic progression Oncogene, 38 (33), 6109-6122 Approaches in high-risk rectal cancer Bioessays, 41 (8), e1900022 Berge LAM, Andreassen BK, Stenehjem BMC Cancer, 19 (1), 488 JS, Larsen IK, Furu K, Juzeniene A, Andersen E, Chollet ME, Baroni M, Pi- Abravan A, Eide HA, Løndalen AM, Roscher I, Heir T, Green A, Veierød MB, notti M, Bernardi F, Skarpen E, Sandset Helland Å, Malinen E (2019) Robsahm TE (2019) PM, Skretting G (2019) Mapping Bone Marrow Response Cardiovascular, antidepressant and The effect of the chemical chaper- in the Vertebral Column by Positron immunosuppressive drug use in one 4-phenylbutyrate on secretion Emission Tomography Following relation to risk of cutaneous mela- and activity of the p.Q160R mis- Radiotherapy and Erlotinib Therapy noma: a protocol for a prospective sense variant of coagulation factor of Lung Cancer case-control study FVII Mol Imaging Biol, 21 (2), 391-398 BMJ Open, 9 (2), e025246 Cell Biosci, 9, 69 Ackermann F, Schink KO, Bruns C, Bergholtz H, Lien TG, Ursin G, Hol- Andersson Y, Inderberg EM, Kvalheim Izsvák Z, Hamra FK, Rosenmund C, men MM, Helland Å, Sørlie T, Haak- G, Herud TM, Engebraaten O, Flat- Garner CC (2019) ensen VD (2019) mark K, Dueland S, Fodstad Ø (2019) Critical role for Piccolo in synaptic A Longitudinal Study of the Associ- Immune stimulatory effect of an- vesicle retrieval ation between Mammographic Den- ti-EpCAM immunotoxin - improved Elife, 8 sity and Gene Expression in Normal overall survival of metastatic col- Breast Tissue orectal cancer patients Aghayan DL, Fretland ÅA, Kazaryan J Mammary Gland Biol Neoplasia, 24 Acta Oncol, 26:1-6 AM, Sahakyan MA, Dagenborg VJ, (2), 163-175 Bjørnbeth BA, Flatmark K, Kristiansen Bains SJ, Abrahamsson H, Flatmark K, R, Edwin B (2019) Blin M, Le Tallec B, Nähse V, Schmidt Dueland S, Hole KH, Seierstad T, Re- Laparoscopic versus open liver M, Brossas C, Millot GA, Prioleau MN, dalen KR, Meltzer S, Ree AH (2019) resection in the posterosuperior Debatisse M (2019) Immunogenic cell death by neo- segments: a sub-group analysis Transcription-dependent regulation adjuvant oxaliplatin and radiation from the OSLO-COMET randomized of replication dynamics modulates protects against metastatic failure in controlled trial genome stability high-risk rectal cancer HPB (Oxford), 21 (11), 1485-1490 Nature Structural & Molecular Biology Cancer Immunol Immunother (in press) 26, 58–66 Alcala N, Leblay N, Gabriel AAG, Mang- Barkovskaya A, Seip K, Hilmarsdot- iante L, Hervas D, Giffon T, Sertier AS, Bowitz Lothe IM, Kleive D, Pomianows- tir B, Maelandsmo GM, Moestue SA, Ferrari A, Derks J, Ghantous A, Delhom- ka E, Cvancarova M, Kure E, Dueland Itkonen HM (2019) me TM, Chabrier A, Cuenin C, Abedi-Ar- S, Gladhaug IP, Labori KJ (2019) O-GlcNAc Transferase Inhibition dekani B, Boland A, Olaso R, Meyer V, Clinical relevance of pancreato- Differentially Affects Breast Cancer Altmuller J, Le Calvez-Kelm F, Durand biliary and intestinal subtypes of Subtypes G, Voegele C, Boyault S, Moonen L, ampullary and duodenal adeno- Sci Rep, 9 (1), 5670 Lemaitre N, Brustugun OT, Lorimier P carcinoma: Pattern of recurrence, et al. (2019) chemotherapy, and survival after Bartolomé-Casado R, Landsverk OJB, Integrative and comparative genom- pancreatoduodenectomy Chauhan SK, Richter L, Phung D, ic analyses identify clinically rele- Pancreatology, 19 (2), 316-324 Greiff V, Risnes LF, Yao Y, Neumann RS, vant pulmonary carcinoid groups Yaqub S, Øyen O, Horneland R, Aan- Boye E, Grallert B (2019) and unveil the supra-carcinoids dahl EM, Paulsen V, Sollid LM, Qiao eIF2α phosphorylation and the regu- Nat Commun, 10 (1), 3407 SW, Baekkevold ES, Jahnsen FL (2019) lation of translation Resident memory CD8 T cells per- Ali M, Foldvari Z, Giannakopoulou Curr Genet (in press) sist for years in human small intes- E, Böschen ML, Strønen E, Yang W, tine Brennecke P, Rasina D, Aubi O, Herzog Toebes M, Schubert B, Kohlbacher O, J Exp Med, 216 (10), 2412-2426 K, Landskron J, Cautain B, Vicente F,

76 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Quintana J, Mestres J, Stechmann B, Heterogeneous radiological re- vation protein (FAP) and basal-type Ellinger B, Brea J, Kolanowski JL, Pi- sponse to neoadjuvant therapy is markers (CK 5/6 and CD44) predicts larski R, Orzaez M, Pineda-Lucena A, associated with poor prognosis prognosis in high-grade invasive Laraia L, Nami F, Zielenkiewicz P, Paruch after resection of colorectal liver urothelial carcinoma of the bladder K, Hansen E, von Kries JP, Neuen- metastases Hum Pathol, 91, 61-68 schwander M, Specker E, Bartunek P et Eur J Surg Oncol, 45 (12), 2340-2346 al. (2019) Camilio KA, Wang MY, Mauseth B, EU-OPENSCREEN: A Novel Collabo- Brunsell TH, Sveen A, Bjørnbeth BA, Waagene S, Kvalheim G, Rekdal Ø, rative Approach to Facilitate Chemi- Røsok BI, Danielsen SA, Brudvik KW, Sveinbjørnsson B, Mælandsmo GM cal Biology Berg KCG, Johannessen B, Cengija (2019) SLAS Discov, 24 (3), 398-413 V, Abildgaard A, Guren MG, Nesbakken Combining the oncolytic peptide A, Lothe RA (2019) LTX-315 with doxorubicin demon- Briem E, Ingthorsson S, Traustadottir High Concordance and Negative strates therapeutic potential in a GA, Hilmarsdottir B, Gudjonsson T Prognostic Impact of RAS/BRAF/ triple-negative breast cancer model (2019) PIK3CA Mutations in Multiple Re- Breast Cancer Res, 21 (1), 9 Application of the D492 Cell Lines sected Colorectal Liver Metastases to Explore Breast Morphogenesis, Clin Colorectal Cancer (in press) Carm KT, Hoff AM, Bakken AC, EMT and Cancer Progression in 3D Axcrona U, Axcrona K, Lothe RA, Culture Brynildsen J, Petäjä L, Myhre PL, Skotheim RI, Løvf M (2019) J Mammary Gland Biol Neoplasia, 24 Lyngbakken MN, Nygård S, Stridsberg Interfocal heterogeneity challenges (2), 139-147 M, Christensen G, Ottesen AH, Pettilä V, the clinical usefulness of molecular Omland T, Røsjø H (2019) classification of primary prostate Brinkman AB, Nik-Zainal S, Simmer F, Circulating Secretoneurin Concen- cancer Rodríguez-González FG, Smid M, Alex- trations After Cardiac Surgery: Data Sci Rep, 9 (1), 13579 androv LB, Butler A, Martin S, Davies H, From the FINNish Acute Kidney Glodzik D, Zou X, Ramakrishna M, Staaf Injury Heart Study Chellappa S, Kushekhar K, Munthe J, Ringnér M, Sieuwerts A, Ferrari A, Crit Care Med, 47 (5), e412-e419 LA, Tjønnfjord GE, Aandahl EM, Ok- Morganella S, Fleischer T, Kristensen kenhaug K, Taskén K (2019) V, Gut M, van de Vijver MJ, Børre- Braadland PR, Ramberg H, Grytli The PI3K p110δ Isoform Inhibitor sen-Dale AL, Richardson AL, Thomas HH, Urbanucci A, Nielsen HK, Guld- Idelalisib Preferentially Inhibits Hu- G, Gut IG et al. (2019) vik IJ, Engedal A, Ketola K, Wang W, man Regulatory T Cell Function Partially methylated domains are Svindland A, Mills IG, Bjartell A, Taskén J Immunol, 202 (5), 1397-1405 hypervariable in breast cancer and KA (2019) Cornillet M, Jansson H, Schaffer M, fuel widespread CpG island hyper- The β2-Adrenergic Receptor Is a methylation Molecular Switch for Neuroendo- Hertwig L, Berglin L, Zimmer CL, Jo- Nat Commun, 10 (1), 1749 crine Transdifferentiation of Prostate hansson H, Ellis E, Isaksson B, Gonza- Cancer Cells lez-Galarza FF, Middleton D, Malmberg Brison O, El-Hilali S, Azar D, Kound- Mol Cancer Res, 17 (11), 2154-2168 KJ, Sparrelid E, Björkström NK (2019) rioukoff S, Schmidt M, Nähse V, Imbalance of Genes Encoding Natu- Jaszczyszyn Y, Lachages AM, Dutrillaux Braadland PR, Urbanucci A (2019) ral Killer Immunoglobulin-Like Re- B, Thermes C, Debatisse M, Chen CL Chromatin reprogramming as an ceptors and Human Leukocyte Anti- (2019) adaptation mechanism in advanced gen in Patients With Biliary Cancer Transcription-mediated organization prostate cancer Gastroenterology, 157 (4), 1067-1080. of the replication initiation program Endocr Relat Cancer, 26 (4), R211-R235 e9 across large genes sets common fragile sites genome-wide Burocziova M, Burdova K, Martinikova Cremaschi A, Argiento R, Shoemaker Nat Commun, 10 (1), 5693 AS, Kasparek P, Kleiblova P, Danielsen K, Peterson C, Vannucci M (2019) SA, Borecka M, Jenikova G, Janečková Hierarchical Normalized Complete- Brudvik KW, Jones RP, Giuliante F, Shin- L, Pavel J, Zemankova P, Schneidero- ly Random Measures for Robust doh J, Passot G, Chung MH, Song J, Li va M, Schwarzova L, Ticha I, Sun XF, Graphical Modeling L, Dagenborg VJ, Fretland ÅA, Røsok Jiraskova K, Liska V, Vodickova L, Vod- Bayesian Anal., 14 (4), 1271-1301 B, De Rose AM, Ardito F, Edwin B, icka P, Sedlacek R, Kleibl Z, Lothe RA, Panettieri E, Larocca LM, Yamashita S, Korinek V, Macurek L (2019) Crosbie EJ, Ryan NAJ, Arends Conrad C, Aloia TA, Poston GJ, Bjørn- Truncated PPM1D impairs stem cell MJ, Bosse T, Burn J, Cornes JM, beth BA, Vauthey JN (2019) response to genotoxic stress and Crawford R, Eccles D, Frayling IM, RAS Mutation Clinical Risk Score to promotes growth of APC-deficient Ghaem-Maghami S, Hampel H, Kauff Predict Survival After Resection of tumors in the mouse colon ND, Kitchener HC, Kitson SJ, Manchan- Colorectal Liver Metastases Cell Death Dis, 10 (11), 818 da R, McMahon RFT, Monahan KJ, Me- Ann Surg, 269 (1), 120-126 non U, Møller P, Möslein G, Rosenthal Calvete J, Larrinaga G, Errarte P, Martín A, Sasieni P, Seif MW, Singh N, Skarrott Brunsell TH, Cengija V, Sveen A, AM, Dotor A, Esquinas C, Nunes-Xavi- P et al. (2019) Bjørnbeth BA, Røsok BI, Brudvik KW, er CE, Pulido R, López JI, Angulo JC The Manchester International Con- Guren MG, Lothe RA, Abildgaard A, (2019) sensus Group recommendations for Nesbakken A (2019) The coexpression of fibroblast acti- the management of gynecological

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 77 Publications cancers in Lynch syndrome mismatch repair variants: findings JM, Nesbakken A, Johannessen B, Genet Med, 21 (10), 2390-2400 from the Prospective Lynch Syn- Lothe RA, Sveen A (2019) (Epub drome Database ahead of print) Debik J, Euceda LR, Lundgren S, Gyth- Genet Med, 22 (1), 15-25 Technical differences between se- feldt HVL, Garred Ø, Borgen E, Enge- quencing and microarray platforms braaten O, Bathen TF, Giskeødegård Dominguez-Valentin M, Seppälä TT, impact transcriptomic subtyping of GF (2019) Sampson JR, Macrae F, Winship I, colorectal cancer Assessing Treatment Response and Evans DG, Scott RJ, Burn J, Möslein Cancer Lett, 469, 246-255 Prognosis by Serum and Tissue G, Bernstein I, Pylvänäinen K, Ren- Metabolomics in Breast Cancer konen-Sinisalo L, Lepistö A, Lindblom Enqvist M, Jacobs B, Junlén HR, Patients A, Plazzer JP, Tjandra D, Thomas H, Schaffer M, Melén CM, Friberg D, Wah- J Proteome Res, 18 (10), 3649-3660 Green K, Lalloo F, Crosbie EJ, Hill J, lin BE, Malmberg KJ (2019) Capella G, Pineda M, Navarro M, Vidal Systemic and Intra-Nodal Activation Della Valle A, Rossi BM, Palmero EI, JB et al. (2019) of NK Cells After Rituximab Mono- Antelo M, Vaccaro CA, López-Kostner Survival by colon cancer stage and therapy for Follicular Lymphoma F, Alvarez K, Cruz-Correa M, Bruno LI, screening interval in Lynch syn- Front Immunol, 10, 2085 Forones NM, Mindiola JAR, Buleje J, drome: a prospective Lynch syn- Spirandelli F, Bohorquez M, Cock-Rada drome database report Escala-Garcia M, Abraham J, Andrulis AM, Sullcahuaman Y, Nascimento I, Hered Cancer Clin Pract, 17, 28 IL, Anton-Culver H, Arndt V, Ashworth Abe-Sandes K, Lino-Silva LS, Petracchi A, Auer PL, Auvinen P, Beckmann F, Mampel A, Rodriguez Y, Rossi NT, Dong X, Zhang R, He J, Lai L, Alolga MW, Beesley J, Behrens S, Benitez J, Yañez CB, Rubio C et al. (2019) RN, Shen S, Zhu Y, You D, Lin L, Chen Bermisheva M, Blomqvist C, Blot W, A snapshot of current genetic test- C, Zhao Y, Duan W, Su L, Shafer A, Bogdanova NV, Bojesen SE, Bolla MK, ing practice in Lynch syndrome: The Salama M, Fleischer T, Bjaanæs MM, Børresen-Dale AL, Brauch H, Brenner results of a representative survey of Karlsson A, Planck M, Wang R, Staaf J, H, Brucker SY, Burwinkel B, Caldas C, 33 Latin American existing centres/ Helland Å, Esteller M, Wei Y, Chen F et Canzian F et al. (2020) registries al. (2019) A network analysis to identify medi- Eur J Cancer, 119, 112-121 Trans-omics biomarker model im- ators of germline-driven differences proves prognostic prediction accu- in breast cancer prognosis Dienstmann R, Villacampa G, Sveen A, racy for early-stage lung adenocar- Nat Commun, 11 (1), 312 Mason MJ, Niedzwiecki D, Nesbakken cinoma A, Moreno V, Warren RS, Lothe RA, Aging (Albany NY), 11 (16), 6312-6335 Eriksson AG, Fallaas Dahl G, Nesbak- Guinney J (2019) ken AJ, Lund KV, Amant F (2019) Relative contribution of clinico- Dörk T, Peterlongo P, Mannermaa A, Endometrial cancer during pregnan- pathological variables, genomic Bolla MK, Wang Q, Dennis J, Ahearn cy: management strategies markers, transcriptomic subtyping T, Andrulis IL, Anton-Culver H, Arndt V, Int J Gynecol Cancer, 29 (7), 1221-1224 and microenvironment features for Aronson KJ, Augustinsson A, Freeman outcome prediction in stage II/III LEB, Beckmann MW, Beeghly-Fadiel A, Escala-Garcia M, Guo Q, Dörk T, Cani- colorectal cancer Behrens S, Bermisheva M, Blomqvist sius S, Keeman R, Dennis J, Beesley Ann Oncol, 30 (10), 1622-1629 C, Bogdanova NV, Bojesen SE, Brauch J, Lecarpentier J, Bolla MK, Wang Q, H, Brenner H, Burwinkel B, Canzian F, Abraham J, Andrulis IL, Anton-Culver H, Dominguez-Valentin M, Nakken S, Kristensen VN, Chan TL, et al. (2019) Arndt V, Auer PL, Beckmann MW, Beh- Tubeuf H, Vodak D, Ekstrøm PO, Two truncating variants in FANCC rens S, Benitez J, Bermisheva M, Bern- Nissen AM, Morak M, Holinski-Feder and breast cancer risk stein L, Blomqvist C, Boeckx B, Bojesen E, Holth A, Capella G, Davidson B, Sci Rep, 9 (1), 12524 SE, Bonanni B, Børresen-Dale AL et Evans DG, Martins A, Møller P, Hovig al. (2019) E (2019) Eide PW, Eilertsen IA, Sveen A, Genome-wide association study of Results of multigene panel testing in Lothe RA (2019) germline variants and breast can- familial cancer cases without ge- Long noncoding RNA MIR31HG is cer-specific mortality netic cause demonstrated by single a bona fide prognostic marker with Br J Cancer, 120 (6), 647-657 gene testing colorectal cancer cell-intrinsic prop- Sci Rep, 9 (1), 18555 erties Fang EF, Hou Y, Lautrup S, Jensen MB, Int J Cancer, 144 (11), 2843-2853 Yang B, SenGupta T, Caponio D, Khezri Dominguez-Valentin M, Sampson JR, R, Demarest TG, Aman Y, Figueroa D, Seppälä TT, Ten Broeke SW, Plazzer JP, Eilertsen IA, Sveen A, Strømme JM, Morevati M, Lee HJ, Kato H, Kassa- Nakken S, Engel C, Aretz S, Jenkins Skotheim RI, Nesbakken A, Lothe RA hun H, Lee JH, Filippelli D, Okur MN, MA, Sunde L, Bernstein I, Capella G, (2018) Mangerich A, Croteau DL, Maezawa Y, Balaguer F, Thomas H, Evans DG, Burn Alternative splicing expands the Lyssiotis CA, Tao J, Yokote K, Rusten J, Greenblatt M, Hovig E, de Vos Tot prognostic impact of KRAS in mi- TE et al. (2019) Nederveen Cappel WH, Sijmons RH, crosatellite stable primary colorectal NAD+ augmentation restores mito- Bertario L, Tibiletti MG, Cavestro GM, cancer phagy and limits accelerated aging Lindblom A, Della Valle A et al. (2019) Int J Cancer, 144 (4), 841-847 in Werner syndrome Cancer risks by gene, age, and gen- Nat Commun, 10 (1), 5284 der in 6350 carriers of pathogenic Eilertsen IA, Moosavi SH, Strømme

78 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Farmer JR, Foldvari Z, Ujhazi B, De Transl Oncol, 12 (7), 951-958 of Disease Study 2016 Ravin SS, Chen K, Bleesing JJH, Lancet Neurol, 18 (5), 439-458 Schuetz C, Al-Herz W, Abraham RS, Forthun RB, Hovland R, Schuster C, Joshi AY, Costa-Carvalho BT, Buchbind- Puntervoll H, Brodal HP, Namløs HM, Gheorghe M, Sandve GK, Khan A, er D, Booth C, Reiff A, Ferguson PJ, Aasheim LB, Meza-Zepeda LA, Chèneby J, Ballester B, Mathelier A Aghamohammadi A, Abolhassani H, Gjertsen BT, Knappskog S, Straume O (2019) Puck JM, Adeli M, Cancrini C, Palma (2019) A map of direct TF-DNA interactions P, Bertaina A, Locatelli F, Di Matteo G, ctDNA detected by ddPCR reveals in the human genome Geha RS et al. (2019) changes in tumour load in metastat- Nucleic Acids Res, 47 (4), e21 Outcomes and Treatment Strategies ic malignant melanoma treated with for Autoimmunity and Hyperinflam- bevacizumab Glaire MA, Domingo E, Sveen A, mation in Patients with RAG Defi- Sci Rep, 9 (1), 17471 Bruun J, Nesbakken A, Nicholson G, ciency Novelli M, Lawson K, Oukrif D, Kildal W, J Allergy Clin Immunol Pract, 7 (6), Fougner C, Bergholtz H, Kuiper R, Danielsen HE, Kerr R, Kerr D, Tomlinson 1970-1985.e4 Norum JH, Sørlie T (2019) I, Lothe RA, Church DN (2019) Claudin-low-like mouse mammary Tumour-infiltrating CD8+ lympho- Ferreira MA, Gamazon ER, Al-Ejeh F, tumors show distinct transcriptomic cytes and colorectal cancer recur- Aittomäki K, Andrulis IL, Anton-Culver patterns uncoupled from genomic rence by tumour and nodal stage H, Arason A, Arndt V, Aronson KJ, Arun drivers Br J Cancer, 121 (6), 474-482 BK, Asseryanis E, Azzollini J, Balmaña Breast Cancer Res, 21 (1), 85 J, Barnes DR, Barrowdale D, Beckmann Global Burden of Disease Cancer MW, Behrens S, Benitez J, Bermisheva Fretland ÅA, Dagenborg VJ, Waaler Collaboration, Fitzmaurice C, Abate D, M, Białkowska K, Blomqvist C, Bogdan- Bjørnelv GM, Aghayan DL, Kazaryan Abbasi N, Abbastabar H, Abd-Allah F, ova NV, Bojesen SE, Bolla MK, Kris- AM, Barkhatov L, Kristiansen R, Fager- Abdel-Rahman O, Abdelalim A, Abdoli tensen VN Borg A et al. (2019) land MW, Edwin B, Andersen MH (2019) A, Abdollahpour I, Abdulle ASM, Abe- Genome-wide association and tran- Quality of life from a randomized be ND, Abraha HN, Abu-Raddad LJ, scriptome studies identify target trial of laparoscopic or open liver Abualhasan A, Adedeji IA, Advani SM, genes and risk loci for breast cancer resection for colorectal liver metas- Afarideh M, Afshari M, Aghaali M, Agius Nat Commun, 10 (1), 1741 tases D, Agrawal S, Ahmadi A, Ahmadian E, Br J Surg, 106 (10), 1372-1380 Ahmadpour E et al. (2019) Flem-Karlsen K, Fodstad Y, Global, Regional, and National Can- Nunes-Xavier CE (2019) Frikstad KM, Molinari E, Thoresen M, cer Incidence, Mortality, Years of B7-H3 immune checkpoint protein in Ramsbottom SA, Hughes F, Letteboer Life Lost, Years Lived With Disabili- human cancer SJF, Gilani S, Schink KO, Stokke ty, and Disability-Adjusted Life-Years Curr Med Chem (in press) T, Geimer S, Pedersen LB, Giles RH, for 29 Cancer Groups, 1990 to 2017: Akhmanova A, Roepman R, Sayer JA, A Systematic Analysis for the Global Flem-Karlsen K, McFadden E, Omar N, Patzke S (2019) Burden of Disease Study Haugen MH, Øy GF, Ryder T, Gulles- A CEP104-CSPP1 Complex Is Re- JAMA Oncol (in press) tad HP, Hermann R, Mælandsmo GM, quired for Formation of Primary Cilia Flørenes VA (2019) Competent in Hedgehog Signaling Goodridge JP, Jacobs B, Saeter- Targeting AXL and the DNA damage Cell Rep, 28 (7), 1907-1922.e6 smoen ML, Clement D, Hammer response pathway as a novel thera- Q, Clancy T, Skarpen E, Brech A, peutic strategy in melanoma Frøysnes IS, Andersson Y, Larsen Landskron J, Grimm C, Pfefferle A, Mol Cancer Ther (in press) SG, Davidson B, Øien JT, Julsrud L, Meza-Zepeda L, Lorenz S, Wiiger Fodstad Ø, Dueland S, Flatmark K MT, Louch WE, Ask EH, Liu LL, Oei Flem-Karlsen K, Tekle C, Øyjord T, (2019) VYS, Kjällquist U, Linnarsson S, Patel Flørenes VA, Mælandsmo GM, Fods- ImmunoPeCa trial: Long-term S, Taskén K, Stenmark H, Malmberg tad Ø, Nunes-Xavier CE (2019) outcome following intraperitoneal KJ (2019) p38 MAPK activation through MOC31PE immunotoxin treatment in Remodeling of secretory lysosomes B7-H3-mediated DUSP10 repression colorectal peritoneal metastasis during education tunes functional promotes chemoresistance Eur J Surg Oncol (in press) potential in NK cells Sci Rep, 9 (1), 5839 Nat Commun, 10 (1), 514 Gaustad JV, Simonsen TG, Wegner Flørenes VA, Flem-Karlsen K, McFad- CS, Rofstad EK (2019) Grigalavicius M, Mastrangelopou- den E, Bergheim IR, Nygaard V, Vascularization, Oxygenation, and lou M, Berg K, Arous D, Ménard M, Nygård V, Farstad IN, Øy GF, Emilsen the Effect of Sunitinib Treatment in Raabe-Henriksen T, Brondz E, Siem E, Giller-Fleten K, Ree AH, Flatmark Pancreatic Ductal Adenocarcinoma S, Görgen A, Edin NFJ, Malinen E, The- K, Gullestad HP, Hermann R, Ryder T, Xenografts odossiou TA (2019) Wernhoff P, Mælandsmo GM (2019) Front Oncol, 9, 845 Proton-dynamic therapy following A Three-dimensional Ex Vivo Viabil- photosensitiser activation by ac- ity Assay Reveals a Strong Correla- GBD 2016 Stroke Collaborators (2019) celerated protons demonstrated tion Between Response to Targeted Global, regional, and national bur- through fluorescence and singlet Inhibitors and Mutation Status in den of stroke, 1990-2016: a system- oxygen production Melanoma Lymph Node Metastases atic analysis for the Global Burden Nat Commun, 10 (1), 3986

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 79 Publications

Grinde MT, Hilmarsdottir B, Tunset FR Inhibitor LY2874455 in FRS2-Am- Helgeland H, Sodeland M, Zoric N, HM, Henriksen IM, Kim J, Haugen MH, plified Liposarcoma Torgersen JS, Grammes F, von Lintig Rye MB, Mælandsmo GM, Moestue Cells, 8 (2) J, Moen T, Kjøglum S, Lien S, Våge DI SA (2019) (2019) Glutamine to proline conversion is Hansem LMK, Huang R, Wegner CS, Genomic and functional gene stud- associated with response to glutam- Simonsen TG, Gaustad JV, Hauge A, ies suggest a key role of beta-caro- inase inhibition in breast cancer Rofstad EK (2019) tene oxygenase 1 like (bco1l) gene Breast Cancer Res, 21 (1), 61 Intratumor Heterogeneity in Intersti- in salmon flesh color tial Fluid Pressure in Cervical and Sci Rep, 9 (1), 20061 Ha TJ, Zhang PGY, Robert R, Yeung J, Pancreatic Carcinoma Xenografts Swanson DJ, Mathelier A, Wasserman Transl Oncol, 12 (8), 1079-1085 Hoem G, Bowitz Larsen K, Øvervatn A, WW, Im S, Itoh M, Kawaji H, Lassmann Brech A, Lamark T, Sjøttem E, Johan- T, Daub CO, Arner E, FANTOM Consor- Hansen EP, Fromm B, Andersen SD, sen T (2019) tium, Carninci P, Hayashizaki Y, Forrest Marcilla A, Andersen KL, Borup A, Wil- The FMRpolyGlycine Protein Me- ARR, Goldowitz D (2019) liams AR, Jex AR, Gasser RB, Young diates Aggregate Formation and Identification of novel cerebellar ND, Hall RS, Stensballe A, Ovchinnikov Toxicity Independent of the CGG developmental transcriptional regu- V, Yan Y, Fredholm M, Thamsborg SM, mRNA Hairpin in a Cellular Model lators with motif activity analysis Nejsum P (2019) for FXTAS BMC Genomics, 20 (1), 718 Exploration of extracellular vesicles Front Genet, 10, 249 from Ascaris suum provides evi- Hagberg G, Fure B, Thommessen B, dence of parasite-host cross talk Holdgaard SG, Cianfanelli V, Pupo E, Ihle-Hansen H, Øksengård AR, Nygård J Extracell Vesicles, 8 (1), 1578116 Lambrughi M, Lubas M, Nielsen JC, S, Pendlebury ST, Beyer MK, Wyller TB, Eibes S, Maiani E, Harder LM, Wesch Ihle-Hansen H (2019) Hauge A, Gaustad JV, Huang R, Si- N, Foged MM, Maeda K, Nazio F, de la Predictors for Favorable Cognitive monsen TG, Wegner CS, Andersen Ballina LR, Dötsch V, Brech A, Frankel Outcome Post-Stroke: A-Seven-Year LMK, Rofstad EK (2019) LB, Jäättelä M, Locatelli F, Barisic M, Follow-Up Study DCE-MRI and Quantitative Histology Andersen JS, Bekker-Jensen S, Lund Dement Geriatr Cogn Disord, 48 (1-2), Reveal Enhanced Vessel Matura- AH, Rogov VV, Papaleo E et al. (2019) 45-55 tion but Impaired Perfusion and Selective autophagy maintains Increased Hypoxia in Bevacizum- centrosome integrity and accurate Halvorsen AR, Ragle Aure M, Õjlert ab-Treated Cervical Carcinoma mitosis by turnover of centriolar ÅK, Brustugun OT, Solberg S, Nebdal Int J Radiat Oncol Biol Phys, 104 (3), satellites D, Helland Å (2019) 666-676 Nat Commun, 10 (1), 4176 Identification of microRNAs involved in pathways which characterize the Hauge S, Macurek L, Syljuåsen RG Huse K (2019) expression subtypes of NSCLC (2019) Expanding the Clinical Cytometry Mol Oncol, 13 (12), 2604-2615 p21 limits S phase DNA damage Toolbox-Receptor Occupancy by caused by the Wee1 inhibitor Mass Cytometry Hamfjord J, Guren TK, Dajani O, MK1775 Cytometry A, 95 (10), 1046-1048 Johansen JS, Glimelius B, Sorbye H, Cell Cycle, 18 (8), 834-847 Pfeiffer P, Lingjærde OC, Tveit KM, Huse K, Wogsland CE, Polikowsky HG, Kure EH, Pallisgaard N, Spindler KG Hausken J, Fretland ÅA, Edwin B, Diggins KE, Smeland EB, Myklebust (2019) Andersen MH, Dagenborg VJ, Bjør- JH, Irish JM (2019) Total circulating cell-free DNA as a nelv GMW, Kristiansen R, Røysland K, Human Germinal Center B Cells Dif- prognostic biomarker in metastatic Kvarstein G, Tønnessen TI (2019) fer from Naïve and Memory B Cells colorectal cancer before first-line Intravenous Patient-controlled An- in CD40 Expression and CD40L-In- oxaliplatin-based chemotherapy algesia Versus Thoracic Epidural duced Signaling Response Ann Oncol, 30 (7), 1088-1095 Analgesia After Open Liver Surgery: Cytometry A, 95 (4), 442-449 A Prospective, Randomized, Con- Handle F, Prekovic S, Helsen C, Van trolled, Noninferiority Trial Ihle-Hansen H, Vigen T, Berge T, Hag- den Broeck T, Smeets E, Moris L, Ee- Ann Surg, 270 (2), 193-199 berg G, Engedal K, Rønning OM, Thom- rlings R, Kharraz SE, Urbanucci A, messen B, Lyngbakken MN, Nygård S, Mills IG, Joniau S, Attard G, Claessens Hausott B, Förste A, Zach F, Mangger Røsjø H, Tveit A, Ihle-Hansen H (2019) F (2019) S, Haugsten EM, Klimaschewski L Carotid Atherosclerosis and Cog- Drivers of AR indifferent anti-andro- (2019) nitive Function in a General Popu- gen resistance in prostate cancer Endocytosis and Transport of lation Aged 63-65 Years: Data from cells Growth Factor Receptors in Pe- the Akershus Cardiac Examination Sci Rep, 9 (1), 13786 ripheral Axon Regeneration: Novel (ACE) 1950 Study Lessons from Neurons Expressing J Alzheimers Dis, 70 (4), 1041-1049 Hanes R, Munthe E, Grad I, Han J, Lysine-Deficient FGF Receptor Type Karlsen I, McCormack E, Meza-Zepe- 1 in vitro Itkonen HM, Urbanucci A, Martin SE, da LA, Stratford EW, Myklebost O Anat Rec (Hoboken), 302 (8), 1268- Khan A, Mathelier A, Thiede B, Walker (2019) 1275 S, Mills IG (2019) Preclinical Evaluation of the Pan-FG- High OGT activity is essential for

80 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 MYC-driven proliferation of prostate Cancer Immunol Res, 7 (3), 355-362 ase-specific T helper cell receptors cancer cells isolated from long term survivors Theranostics, 9 (8), 2183-2197 Juraleviciute M, Pozniak J, Nsengimana after cancer vaccination J, Harland M, Randerson-Moor J, Wer- Oncoimmunology, 8 (4), e1565236 Jacobs B, Pfefferle A, Clement D, nhoff P, Bassarova A, Øy GF, Trøen G, Berg-Larsen A, Saetersmoen ML, Flørenes VA, Bishop DT, Herlyn M, New- Köksal H, Dillard P, Josefsson SE, Lorenz S, Wiiger MT, Goodridge JP, ton-Bishop J, Slipicevic A (2019) Maggadottir SM, Pollmann S, Fåne A, Malmberg KJ (2018) MX 2 is a novel regulator of cell Blaker YN, Beiske K, Huse K, Kolstad Induction of the BIM Short Splice cycle in melanoma cells A, Holte H, Kvalheim G, Smeland EB, Variant Sensitizes Proliferating NK Pigment Cell Melanoma Res (Epub Myklebust JH, Inderberg EM, Wälchli Cells to IL-15 Withdrawal ahead of print) S (2019) J Immunol, 202 (3), 736-746 Preclinical development of CD- Kanduri C, Bock C, Gundersen S, Hov- 37CAR T-cell therapy for treatment Jerjes W, Hamdoon Z, Berg K, Høgset ig E, Sandve GK (2019) of B-cell lymphoma A, Hopper C (2019) Colocalization analyses of genomic Blood Adv, 3 (8), 1230-1243 Recurrent chondroblastic osteosar- elements: approaches, recommen- coma of the right mandible subject- dations and challenges Lai X, Geier OM, Fleischer T, Garred ed to photochemical internalization Bioinformatics, 35 (9), 1615-1624 Ø, Borgen E, Funke SW, Kumar S, Photodiagnosis Photodyn Ther, 27, Rognes ME, Seierstad T, Børre- 288-290 Khezri R, Rusten TE (2019) sen-Dale AL, Kristensen VN, Enge- Autophagy and Tumorigenesis in braaten O, Köhn-Luque A, Frigessi A Jiang X, Finucane HK, Schumacher FR, Drosophila (2019) Schmit SL, Tyrer JP, Han Y, Michailidou Adv Exp Med Biol, 1167, 113-127 Toward Personalized Computer Sim- K, Lesseur C, Kuchenbaecker KB, Den- ulation of Breast Cancer Treatment: nis J, Conti DV, Casey G, Gaudet MM, Kotsopoulos J, Lubinski J, Lynch HT, A Multiscale Pharmacokinetic and Huyghe JR, Albanes D, Aldrich MC, Tung N, Armel S, Senter L, Singer CF, Pharmacodynamic Model Informed Andrew AS, Andrulis IL, Anton-Culver H, Fruscio R, Couch F, Weitzel JN, Karlan by Multitype Patient Data Antoniou AC, Antonenkova NN, Arnold B, Foulkes WD, Moller P, Eisen A, Cancer Res, 79 (16), 4293-4304 SM, Aronson KJ, Arun BK, Kristensen Ainsworth P, Neuhausen SL, Olopade O, VN, Bandera EV et al. (2019) Sun P, Gronwald J, Narod SA, Heredi- Lampignano R, Neumann MHD, Weber Shared heritability and functional tary Breast Cancer Clinical Study Group S, Kloten V, Herdean A, Voss T, Groelz enrichment across six solid cancers (2019) D, Babayan A, Tibbesma M, Schlump- Nat Commun, 10 (1), 431 Oophorectomy and risk of contra- berger M, Chemi F, Rothwell DG, lateral breast cancer among BRCA1 Wikman H, Galizzi JP, Bergheim IR, Johansson HJ, Socciarelli F, Vacanti and BRCA2 mutation carriers Russnes H, Mussolin B, Bonin S, Voigt NM, Haugen MH, Zhu Y, Siavelis I, Breast Cancer Res Treat, 175 (2), 443- C, Musa H, Pinzani P, Lianidou E, Brady Fernandez-Woodbridge A, Aure MR, 449 G, Speicher MR, Pantel K et al. (2019) Sennblad B, Vesterlund M, Branca RM, Multicenter Evaluation of Circulating Orre LM, Huss M, Fredlund E, Beraki Kraby MR, Opdahl S, Russnes HG, Cell-Free DNA Extraction and Down- E, Garred Ø, Boekel J, Sauer T, Zhao Bofin AM (2019) stream Analyses for the Develop- W, Nord S, Höglander EK, Jans DC, Microvessel density in breast can- ment of Standardized (Pre)analytical Brismar H, Haukaas TH, Bathen TF et cer: the impact of field area on prog- Work Flows al. (2019) nostic informativeness Clin Chem (in press) Breast cancer quantitative proteome J Clin Pathol, 72 (4), 304-310 and proteogenomic landscape Landsverk HB, Sandquist LE, Sri- Nat Commun, 10 (1), 1600 Kryeziu K, Bruun J, Guren TK, Sveen dhara SC, Rødland GE, Sabino JC, de A, Lothe RA (2019) Almeida SF, Grallert B, Trinkle-Mulcahy Jonsson M, Fjeldbo CS, Holm R, Combination therapies with HSP90 L, Syljuåsen RG (2019) Stokke T, Kristensen GB, Lyng H inhibitors against colorectal cancer Regulation of ATR activity via the (2019) Biochim Biophys Acta Rev Cancer, 1871 RNA polymerase II associated fac- Mitochondrial Function of CKS2 On- (2), 240-247 tors CDC73 and PNUTS-PP1 coprotein Links Oxidative Phosphor- Nucleic Acids Res, 47 (4), 1797-1813 ylation with Cell Division in Chemo- Kumar S, Gu Y, Abudu YP, Bruun JA, radioresistant Cervical Cancer Jain A, Farzam F, Mudd M, Anonsen Larsen LK, Lind GE, Guldberg P, Dahl Neoplasia, 21 (4), 353-362 JH, Rusten TE, Kasof G, Ktistakis N, C (2019) Lidke KA, Johansen T, Deretic V (2019) DNA-Methylation-Based Detection Josefsson SE, Beiske K, Blaker YN, Phosphorylation of Syntaxin 17 by of Urological Cancer in Urine: Over- Førsund MS, Holte H, Østenstad B, TBK1 Controls Autophagy Initiation view of Biomarkers and Consider- Kimby E, Köksal H, Wälchli S, Bai B, Dev Cell, 49 (1), 130-144.e6 ations on Biomarker Design, Source Smeland EB, Levy R, Kolstad A, Huse of DNA, and Detection Technologies K, Myklebust JH (2019) Kyte JA, Fåne A, Pule M, Gaudernack Int J Mol Sci, 20 (11) TIGIT and PD-1 Mark Intratumoral T G (2019) Cells with Reduced Effector Function Transient redirection of T cells for Lee YS, Krishnan A, Oughtred R, Rust in B-cell Non-Hodgkin Lymphoma adoptive cell therapy with telomer- J, Chang CS, Ryu J, Kristensen VN,

INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 81 Publications

Dolinski K, Theesfeld CL, Troyanskaya A, Almeida R, Lothe RA, David L, Bru- Giskeødegård GF (2019) OG (2019) un J (2019 – Epub ahead of print) Historical Biobanks in Breast Can- A Computational Framework for Digital image analysis of multiplex cer Metabolomics- Challenges and Genome-wide Characterization of fluorescence IHC in colorectal can- Opportunities the Human Disease Landscape cer recognizes the prognostic value Metabolites, 9 (11) Cell Syst, 8 (2), 152-162.e6 of CDX2 and its negative correlation with SOX2 Malt EA, Juhasz K, Frengen A, Wangen- Lie-Jensen A, Ivanauskiene K, Lab Invest, 100 (1), 120-134 steen T, Emilsen NM, Hansen B, Aga- Malerød L, Jain A, Tan KW, Laerdahl fonov O, Nilsen HL (2019) JK, Liestøl K, Stenmark H, Haglund K Luhr M, Torgersen ML, Szalai P, Neuropsychiatric phenotype in rela- (2019) Hashim A, Brech A, Staerk J, Engedal tion to gene variants in the hemizy- Centralspindlin Recruits ALIX to the N (2019) gous allele in 3q29 deletion carriers: Midbody during Cytokinetic Abscis- The kinase PERK and the transcrip- A case series sion in Drosophila via a Mechanism tion factor ATF4 play distinct and es- Mol Genet Genomic Med, 7 (9), e889 Analogous to Virus Budding sential roles in autophagy resulting Curr Biol, 29 (20), 3538-3548.e7 from tunicamycin-induced ER stress Marcuello M, Vymetalkova V, Neves J Biol Chem, 294 (20), 8197-8217 RPL, Duran-Sanchon S, Vedeld HM, Lien VT, Kristiansen MK, Pettersen S, Tham E, van Dalum G, Flügen G, Gar- Haugen MH, Olberg DE, Waaler J, Lund-Andersen C, Nakken S, Nygård cia-Barberan V, Fijneman RJ, Castells Klaveness J (2019) S, Fromm B, Aasheim LB, Davidson A, Vodicka P, Lind GE, Stoecklein NH, Towards dual inhibitors of the MET B, Julsrud L, Abrahamsen TW, Kris- Heitzer E, Gironella M (2019) kinase and WNT signaling pathway; tensen AT, Dybdahl B, Larsen SG, Circulating biomarkers for early design, synthesis and biological Hovig E, Flatmark K (2019) detection and clinical management evaluation Integrative genomic analysis of of colorectal cancer RSC Adv., 9 (63), 37092-37100 peritoneal malignant mesothelioma: Mol Aspects Med, 69, 107-122 understanding a case with extraordi- Lien VT, Pettersen S, Haugen MH, nary chemotherapy response Mauseth B, Camilio KA, Shi J, Ham- Olberg DE, Maelandsmo GM, Klave- Cold Spring Harb Mol Case Stud, 5 (2) marström CL, Rekdal Ø, Sveinbjørnsson ness J (2019) B, Line PD (2019) Design, synthesis and biological Lund KV, Simonsen TG, Kristensen The Novel Oncolytic Compound evaluation of 6-substituted quino- GB, Rofstad EK (2019) LTX-401 Induces Antitumor Immune lines derived from cabozantinib as Pharmacokinetic analysis of DCE- Responses in Experimental Hepato- c-Met inhibitors MRI data of locally advanced cervi- cellular Carcinoma Arch Pharm (Weinheim), 352 (9), cal carcinoma with the Brix model Mol Ther Oncolytics, 14, 139-148 e1900101 Acta Oncol, 58 (6), 828-837 Mavaddat N, Michailidou K, Dennis J, Lilleborge M, Falk RS, Russnes H, Lunde NN, Gregersen I, Ueland T, Lush M, Fachal L, Lee A, Tyrer JP, Chen Sauer T, Ursin G, Hofvind S (2019) Shetelig C, Holm S, Kong XY, Michelsen TH, Wang Q, Bolla MK, Yang X, Adank Risk of breast cancer by prior AE, Otterdal K, Yndestad A, Broch MA, Ahearn T, Aittomäki K, Allen J, An- screening results among women K, Gullestad L, Nyman TA, Bendz B, drulis IL, Anton-Culver H, Antonenkova participating in BreastScreen Nor- Eritsland J, Hoffmann P, Skagen K, NN, Arndt V, Aronson KJ, Auer PL, Au- way Gonçalves I, Nilsson J, Grenegård M, vinen P, Barrdahl M, Beane Freeman LE, Cancer, 125 (19), 3330-3337 Poreba M, Drag M, Seljeflot I, Spor- Børresen-Dale AB, Beckmann MW et sheim B, Espevik T, Skjelland M et al. al. (2019) Lindholm EM, Leivonen SK, Undlien (2019) Polygenic Risk Scores for Predic- E, Nebdal D, Git A, Caldas C, Børre- Legumain is upregulated in acute tion of Breast Cancer and Breast sen-Dale AL, Kleivi K (2019) cardiovascular events and associ- Cancer Subtypes miR-342-5p as a Potential Regulator ated with improved outcome - po- Am J Hum Genet, 104 (1), 21-34 of HER2 Breast Cancer Cell Growth tentially related to anti-inflammatory Microrna, 8 (2), 155-165 effects on macrophages Mehto S, Jena KK, Nath P, Chauhan S, Atherosclerosis (in press) Kolapalli SP, Das SK, Sahoo PK, Jain A, Lindholm EM, Ragle Aure M, Hau- Taylor GA, Chauhan S (2019) gen MH, Kleivi Sahlberg K, Kris- Løvf M, Zhao S, Axcrona U, Johan- The Crohn’s Disease Risk Factor tensen VN, Nebdal D, Børresen-Dale nessen B, Bakken AC, Carm KT, IRGM Limits NLRP3 Inflammasome AL, Lingjaerde OC, Engebraaten O Hoff AM, Myklebost O, Meza-Zepe- Activation by Impeding Its Assembly (2019) da LA, Lie AK, Axcrona K, Lothe RA, and by Mediating Its Selective Au- miRNA expression changes during Skotheim RI (2018) tophagy the course of neoadjuvant bevaci- Multifocal Primary Prostate Cancer Mol Cell, 73 (3), 429-445.e7 zumab and chemotherapy treatment Exhibits High Degree of Genomic in breast cancer Heterogeneity Meltzer S, Bakke KM, Rød KL, Negård Mol Oncol, 13 (10), 2278-2296 Eur Urol, 75 (3), 498-505 A, Flatmark K, Solbakken AM, Kris- tensen AT, Fuglestad AJ, Kersten C, Lopes N, Bergsland CH, Bjørnslett Madssen TS, Cao MD, Pladsen AV, Dueland S, Seierstad T, Hole KH, Lycka- M, Pellinen T, Svindland A, Nesbakken Ottestad L, Sahlberg KK, Bathen TF, nder LG, Larsen FO, Schou JV, Patrick

82 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 Brown D, Abrahamsson H, Redalen Mensali N, Myhre MR, Dillard P, Poll- can lumican improves survival and KR, Ree AH (2019) mann S, Gaudernack G, Kvalheim G, counteracts cardiac dilatation and Sex-related differences in primary Wälchli S, Inderberg EM (2019) failure in mice subjected to pressure metastatic site in rectal cancer; as- Preclinical assessment of transient- overload sociated with hemodynamic factors? ly TCR redirected T cells for solid Sci Rep, 9 (1), 9206 Clin Transl Radiat Oncol, 21, 5-10 tumour immunotherapy Cancer Immunol Immunother, 68 (8), Mukhopadhyay UK, Oturkar CC, Ad- Meltzer S, Bjørnetrø T, Lyckander LG, 1235-1243 ams C, Wickramasekera N, Bansal Flatmark K, Dueland S, Samiappan R, S, Medisetty R, Miller A, Swetzig WM, Johansen C, Kalanxhi E, Ree AH, Re- Mesquita P, Freire AF, Lopes N, Gomes Silwal-Pandit L, Børresen-Dale AL, dalen KR (2019) R, Azevedo D, Barros R, Pereira B, Ca- Creighton CJ, Park JH, Konduri SD, Circulating Exosomal miR-141-3p vadas B, Pópulo H, Boaventura P, David Mukhopadhyay A, Caradori A, Omilian and miR-375 in Metastatic Progres- L, Pereira L, Almeida R (2019) A, Bshara W, Kaipparettu BA, Das GM sion of Rectal Cancer Expression and Clinical Relevance (2019) Transl Oncol, 12 (8), 1038-1044 of SOX9 in Gastric Cancer TP53 Status as a Determinant of Dis Markers, 2019, 8267021 Pro- vs Anti-Tumorigenic Effects of Menden MP, Wang D, Mason MJ, Estrogen Receptor-Beta in Breast Szalai B, Bulusu KC, Guan Y, Yu T, Metcalfe K, Eisen A, Senter L, Armel S, Cancer Kang J, Jeon M, Wolfinger R, Nguyen T, Bordeleau L, Meschino WS, Pal T, Lynch J Natl Cancer Inst, 111 (11), 1202-1215 Zaslavskiy M, AstraZeneca-Sanger Drug HT, Tung NM, Kwong A, Ainsworth P, Combination DREAM Consortium, Jang Karlan B, Moller P, Eng C, Weitzel JN, Møller P, Dominguez-Valentin M, IS, Ghazoui Z, Ahsen ME, Vogel R, Neto Sun P, Lubinski J, Narod SA, Hereditary Rødland EA, Hovig E (2019) EC, Norman T, Tang EKY, Garnett MJ, Breast Cancer Clinical Study Group Causes for Frequent Pathogenic Veroli GYD, Fawell S, Hovig E, Stolo- (2019) BRCA1 Variants Include Low Pen- vitzky G, Guinney J et al. (2019) International trends in the uptake etrance in Fertile Ages, Recurrent Community assessment to advance of cancer risk reduction strategies De-Novo Mutations and Genetic computational prediction of cancer in women with a BRCA1 or BRCA2 Drift drug combinations in a pharmacog- mutation Cancers (Basel), 11 (2) enomic screen Br J Cancer, 121 (1), 15-21 Nat Commun, 10 (1), 2674 Namløs HM, Boye K, Meza-Zepeda Mingo J, Luna S, Gaafar A, LA (2019) Menon U, Vedsted P, Zalounina Falborg Nunes-Xavier CE, Torices L, Mosteiro Cell-free DNA in blood as a non- A, Jensen H, Harrison S, Reguilon I, L, Ruiz R, Guerra I, Llarena R, Angulo invasive insight into the sarcoma Barisic A, Bergin RJ, Brewster DH, But- JC, López JI, Pulido R (2019) genome ler J, Brustugun OT, Bucher O, Cairn- Precise definition of PTEN C-termi- Mol Aspects Med, 100827 (in press) duff V, Gavin A, Grunfeld E, Harland E, nal epitopes and its implications in Kalsi J, Knudsen AK, Lambe M, Law RJ, clinical oncology Napoli E, Cessna JT, Fitzgerald R, Lin Y, Malmberg M, Turner D, Neal RD, NPJ Precis Oncol, 3, 11 Pibida L, Collé R, Laureano-Pérez L, White V et al. (2019) Zimmerman BE, Bergeron DE (2019) Time intervals and routes to diag- Miranda A, Hamilton PT, Zhang AW, Primary standardization of 224Ra ac- nosis for lung cancer in 10 jurisdic- Pattnaik S, Becht E, Mezheyeuski A, tivity by liquid scintillation counting tions: cross-sectional study find- Bruun J, Micke P, de Reynies A, Nelson Appl Radiat Isot, 155, 108933 ings from the International Cancer BH (2019) Benchmarking Partnership (ICBP) Cancer stemness, intratumoral het- Ney, A., Mahamed, I., Garcia-Sampe- BMJ Open, 9 (11), e025895 erogeneity, and immune response dro, A., Selbo, P. K., Sancho, P., Mac- across cancers Robert, A. J., Pereira, S. P., Acedo, P. Mensali N, Dillard P, Hebeisen M, Lo- Proc Natl Acad Sci U S A, 116 (18), (2019) renz S, Theodossiou T, Myhre MR, 9020-9029 Combination light-based therapies Fåne A, Gaudernack G, Kvalheim G, to treat pancreatic cancer: a proof of Myklebust JH, Inderberg EM, Wälchli Moghimi SM, Simberg D, Skotland T, concept. Proc. SPIE, 11070. S (2019) Yaghmur A, Hunter AC (2019) NK cells specifically TCR-dressed to The Interplay Between Blood Neckmann U, Wolowczyk C, Hall M, Al- kill cancer cells Proteins, Complement, and Mac- maas E, Ren J, Zhao S, Johannessen EBioMedicine, 40, 106-117 rophages on Nanomedicine Perfor- B, Skotheim RI, Bjørkøy G, Ten Dijke P, mance and Responses Holien T (2019) Mensali N, Grenov A, Pati NB, Dillard P, J Pharmacol Exp Ther, 370 (3), 581-592 GREM1 is associated with metasta- Myhre MR, Gaudernack G, Kvalheim sis and predicts poor prognosis in G, Inderberg EM, Bakke O, Wälchli S Mohammadzadeh N, Lunde IG, An- ER-negative breast cancer patients (2019) denæs K, Strand ME, Aronsen JM, Cell Commun Signal, 17 (1), 140 Antigen-delivery through invariant Skrbic B, Marstein HS, Bandlien C, chain (CD74) boosts CD8 and CD4 T Nygård S, Gorham J, Sjaastad I, Newman AM, Steen CB, Liu CL, Gen- cell immunity Chakravarti S, Christensen G, Enge- tles AJ, Chaudhuri AA, Scherer F, Kho- Oncoimmunology, 8 (3), 1558663 bretsen KVT, Tønnessen T (2019) dadoust MS, Esfahani MS, Luca BA, The extracellular matrix proteogly- Steiner D, Diehn M, Alizadeh AA. 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Nov;575(7781):60-61 OT, Lingjaerde OC, Helland Å (2019) Souza GA, Vartdal F, Lossius A (2019) The immune microenvironment in Persistence of intrathecal oligo- Woldemariam NT, Agafonov O, Høy- non-small cell lung cancer is predic- clonal B cells and IgG in multiple heim B, Houston RD, Taggart JB, Andre- tive of prognosis after surgery sclerosis assen R (2019) Mol Oncol, 13 (5), 1166-1179 J Neuroimmunol, 333, 576966 Expanding the miRNA Repertoire in Atlantic Salmon; Discovery of Aasen T, Leithe E, Graham SV, Kamer- Totland MZ, Rasmussen NL, Knud- IsomiRs and miRNAs Highly Ex- itsch P, Mayán MD, Mesnil M, Pogoda K, sen LM, Leithe E (2019) pressed in Different Tissues and Tabernero A (2019) Regulation of gap junction intercel- Developmental Stages Connexins in cancer: bridging the lular communication by connexin Cells, 8 (1) gap to the clinic ubiquitination: physiological and Oncogene, 38 (23), 4429-4451 pathophysiological implications Zakrzewska M, Opalinski L, Haugsten Cell Mol Life Sci (in press) EM, Otlewski J, Wiedlocha A (2019) Crosstalk between p38 and Erk 1/2 Umu SU, Langseth H, Keller A, Meese E, in Downregulation of FGF1-Induced Publications 2020 Helland Å, Lyle R, Rounge TB (2020) Signaling and in press A 10-year prediagnostic follow-up Int J Mol Sci, 20 (8) study shows that serum RNA signals Bai B, Myklebust JH, Wälchli S Zhang R, Lai L, Dong X, He J, You D, are highly dynamic in lung carcino- (2020) Chen C, Lin L, Zhu Y, Huang H, Shen genesis Gene Editing in B-Lymphoma Cell S, Wei L, Chen X, Guo Y, Liu L, Su L, Mol Oncol, 14 (2), 235-247 Lines Using CRISPR/Cas9 Technol- Shafer A, Moran S, Fleischer T, Bjaan- ogy Vaccaro CA, López-Kostner F, Adriana aes MM, Karlsson A, Planck M, Staaf Methods Mol Biol, 2115, 445-454 DV, Palmero EI, Rossi BM, Antelo M, J, Helland Å, Esteller M, Wei Y et al. 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(2019) Mol Oncol, 13 (5), 1235-1248 Chu DT, Phuong TNT, Tien NLB, Tran From colorectal cancer pattern to DK, Thanh VV, Quang TL, Truong DT, Zhang R, Lai L, He J, Chen C, You D, the characterization of individuals at Pham VH, Ngoc VTN, Chu-Dinh T, Duan W, Dong X, Zhu Y, Lin L, Shen risk: Picture for genetic research in Kushekhar K (2020) S, Guo Y, Su L, Shafer A, Moran S, Latin America An Update on the Progress of Isola- Int J Cancer, 145 (2), 318-326 Fleischer T, Bjaanæs MM, Karlsson

88 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2019 tion, Culture, Storage, and Clinical Soluble AXL as a marker of disease Harnessing the Antiviral-Type Re- Application of Human Bone Marrow progression and survival in mela- sponses Induced by Immunostimu- Mesenchymal Stem/Stromal Cells noma latory siRNAs for Cancer Immuno- Int J Mol Sci, 21 (3) PLoS One, 15 (1), e0227187 therapy Methods Mol Biol, 2115, 281-287 Dal NK, Kocere A, Wohlmann J, Van Fornes O, Castro-Mondragon JA, Khan Herck S, Bauer TA, Resseguier J, Ba- A, van der Lee R, Zhang X, Richmond Jakobi AJ, Huber ST, Mortensen gherifam S, Hyldmo H, Barz M, De PA, Modi BP, Correard S, Gheorghe M, SA, Schultz SW, Palara A, Kuhm T, Geest BG, Fenaroli F (2020) Baranašić D, Santana-Garcia W, Tan G, Shrestha BK, Lamark T, Hagen WJH, Zebrafish Embryos Allow Prediction Chèneby J, Ballester B, Parcy F, San- Wilmanns M, Johansen T, Brech A, of Nanoparticle Circulation Times in delin A, Lenhard B, Wasserman WW, Sachse C (2020) Mice and Facilitate Quantification of Mathelier A (2020) Structural basis of p62/SQSTM1 Nanoparticle-Cell Interactions JASPAR 2020: update of the helical filaments and their role in Small, 16 (5), e1906719 open-access database of transcrip- cellular cargo uptake tion factor binding profiles Nat Commun, 11 (1), 440 Darvekar S, Juzenas P, Oksvold M, Nucleic Acids Res, 48 (D1), D87-D92 Kleinauskas A, Holien T, Christensen E, Jakobsen LH, Ellin F, Smeland KB, Stokke T, Sioud M, Peng Q (2020) Fromm B, Domanska D, Høye E, Wästerlid T, Christensen JH, Jørgensen Selective Killing of Activated T Cells Ovchinnikov V, Kang W, Aparicio-Puerta JM, Josefsson PL, Øvlisen AK, Holte H, by 5-Aminolevulinic Acid Mediated E, Johansen M, Flatmark K, Mathelier Blaker YN, Grauslund JH, Bjørn J, Mo- Photodynamic Effect: Potential Im- A, Hovig E, Hackenberg M, Friedländer lin D, Lagerlöf I, Smedby KE, Colvin K, provement of Extracorporeal Pho- MR, Peterson KJ (2020) Thanarajasingam G, Maurer MJ, Haber- topheresis MirGeneDB 2.0: the metazoan mi- mann TM, Song KW, Zhu KY, Gerrie AS, Cancers 2020, 12(2), 377 croRNA complement Cheah CY, El-Galaly TC (2020) Nucleic Acids Res, 48 (D1), D132-D141 Minimal relapse risk and early nor- Escala-Garcia M, Abraham J, Andrulis malization of survival for patients IL, Anton-Culver H, Arndt V, Ashworth Fromm B, Domanska D, Høye E, with Burkitt lymphoma treated with A, Auer PL, Auvinen P, Beckmann Ovchinnikov V, Kang W, Aparicio-Puer- intensive immunochemotherapy: an MW, Beesley J, Behrens S, Benitez J, ta E, Johansen M, Flatmark K, international study of 264 real-world Bermisheva M, Blomqvist C, Blot W, Mathelier A, Hovig E, Hackenberg M, patients Bogdanova NV, Bojesen SE, Bolla MK, Friedländer MR, Peterson KJ (2020) Br J Haematol (in press) Børresen-Dale AL, Brauch H, Brenner MirGeneDB 2.0: the metazoan mi- H, Brucker SY, Burwinkel B, Caldas C, croRNA complement Jerjes W, Hamdoon Z, Berg K, Høgset Canzian F et al. (2020) Nucleic Acids Res, 48 (D1), D1172 A, Hopper C (2020) A network analysis to identify medi- Apparent Complete Response of a ators of germline-driven differences Georgiesh T, Boye K, Bjerkehagen B Treatment Refractory and Recurrent in breast cancer prognosis (2020) Squamous Cell Carcinoma Lesion Nat Commun, 11 (1), 312 A novel risk score to predict early to Photochemical Internalization: A and late recurrence in solitary fi- Clinical Case Study Fachal L, Aschard H, Beesley J, Barnes brous tumour Photochem Photobiol (in press) DR, Allen J, Kar S, Pooley KA, Dennis Histopathology (in press) J, Michailidou K, Turman C, Soucy P, Knutsen E, Lellahi SM, Aure MR, Nord Lemaçon A, Lush M, Tyrer JP, Ghous- Goleva-Fjellet S, Bjurholt AM, Kure EH, S, Fismen S, Larsen KB, Gabriel MT, saini M, Moradi Marjaneh M, Jiang X, Larsen IK, Støren Ø, Sæbø M (2020) Hedberg A, Bjørklund SS, Oslo Breast Agata S, Aittomäki K, Alonso MR, An- Distribution of allele frequencies Cancer Research Consortium (OSBRE- drulis IL, Anton-Culver H, Antonenkova for genes associated with physical AC), Bofin AM, Mælandsmo GM, Sør- NN, Arason A, Arndt V et al. (2020) activity and/or physical capacity in lie T, Mortensen ES, Perander M (2020) Fine-mapping of 150 breast cancer a homogenous Norwegian cohort- a The expression of the long NEAT1_2 risk regions identifies 191 likely cross-sectional study isoform is associated with human target genes BMC Genet, 21 (1), 8 epidermal growth factor receptor Nat Genet, 52 (1), 56-73 2-positive breast cancers Hovda T, Holen ÅS, Lång K, Albertsen Sci Rep, 10 (1), 1277 Eilertsen IA, Moosavi SH, Strømme JL, Bjørndal H, Brandal SHB, Sahlberg JM, Nesbakken A, Johannessen B, KK, Skaane P, Suhrke P, Hofvind S Lopes N, Bergsland CH, Bjørnslett Lothe RA, Sveen A (2020) (2020) M, Pellinen T, Svindland A, Nesbakken Technical differences between se- Interval and Consecutive Round A, Almeida R, Lothe RA, David L, Bru- quencing and microarray platforms Breast Cancer after Digital Breast un J (2020) impact transcriptomic subtyping of Tomosynthesis and Synthetic 2D Digital image analysis of multiplex colorectal cancer Mammography versus Standard 2D fluorescence IHC in colorectal can- Cancer Lett, 469, 246-255 Digital Mammography in Breast- cer recognizes the prognostic value Screen Norway of CDX2 and its negative correlation Flem-Karlsen K, Nyakas M, Farstad IN, Radiology, 294 (2), 256-264 with SOX2 McFadden E, Wernhoff P, Jacobsen KD, Lab Invest, 100 (1), 120-134 Flørenes VA, Mælandsmo GM (2020) Iversen PO, Sioud M (2020)

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Malenge MM, Patzke S, Ree AH, Stok- Receptor Targeted Photodynamic Umu SU, Langseth H, Keller A, Meese ke T, Ceuppens P, Dahle J, Repetto-Lla- Therapy: The Effect of Fluence Rate E, Helland Å, Lyle R, Rounge TB (2020) mazares AHV. (2020) Cancers (Basel), 12 (1) A 10-year prediagnostic follow-up 177Lu-lilotomab satetraxetan has the study shows that serum RNA sig- potential to counteract resistance Rein ID, Notø HØ, Bostad M, Huse nals are highly dynamic in lung car- to rituximab in rituximab resistant K, Stokke T (2020) cinogenesis non-Hodgkin lymphoma. Cell Cycle Analysis and Relevance Mol Oncol, 14 (2), 235-247 J Nuclear Medicine (in press) for Single-Cell Gating in Mass Cy- tometry Wälchli S, Sioud M (2020) Mensali N, Myhre MR, Dillard P, Poll- Cytometry A Next Generation of Adoptive T Cell mann S, Gaudernack G, Kvalheim G, Therapy Using CRISPR/Cas9 Tech- Wälchli S, Inderberg EM (2020) Simonsen TG, Gaustad JV, Rofstad nology: Universal or Boosted? Correction to: Preclinical assess- EK (2020) Methods Mol Biol, 2115, 407-417 ment of transiently TCR redirected T Bevacizumab treatment of meninge- cells for solid tumour immunother- al melanoma metastases apy J Transl Med, 18 (1), 13 Cancer Immunol Immunother, 69 (1), 159-161 Sioud M (2020) Unleashing the Therapeutic Poten- Meås HZ, Haug M, Beckwith MS, Louet tial of Dendritic and T Cell Therapies C, Ryan L, Hu Z, Landskron J, Nordbø Using RNA Interference SA, Taskén K, Yin H, Damås JK, Flo TH Methods Mol Biol, 2115, 259-280 (2020) Sensing of HIV-1 by TLR8 activates Sioud M (2020) human T cells and reverses latency RNA and CRISPR Interferences: Nat Commun, 11 (1), 147 Past, Present, and Future Perspec- tives Mobergslien A, Sioud M (2020) Methods Mol Biol, 2115, 1-22 Exploring 5’-Biotinylation of the Sense Strand to Improve siRNA Sioud M (2020) Specificity and Potency Optimized siRNA Delivery into Pri- Methods Mol Biol, 2115, 163-170 mary Immune Cells Using Electro- poration Nakstad ER, Stær-Jensen H, Wimmer Methods Mol Biol, 2115, 119-131 H, Henriksen J, Alteheld LH, Reichen- bach A, Drægni T, Šaltytė-Benth J, Šošić L, Selbo PK, Kotkowska ZK, Wilson JA, Etholm L, Øijordsbakken Kündig TM, Høgset A, Johansen P M, Eritsland J, Seljeflot I, Jacobsen D, (2020) Andersen GØ, Lundqvist C, Sunde K Photochemical Internalization: Light (2020) Paves Way for New Cancer Chemo- Late awakening, prognostic fac- therapies and Vaccines tors and long-term outcome in Cancers (Basel), 12 (1) out-of-hospital cardiac arrest - results of the prospective Norwegian Stenberg VY, Juzeniene A, Chen Q, Cardio-Respiratory Arrest Study Yang X, Bruland ØS, Larsen RH (2020) (NORCAST) Preparation of the alpha-emitting Resuscitation (in press) prostate-specific membrane antigen targeted radioligand [212 Pb]Pb- Omsland M, Andresen V, Gullaksen SE, NG001 for prostate cancer Ayuda-Durán P, Popa M, Hovland R, J Labelled Comp Radiopharm Brendehaug A, Enserink J, McCor- mack E, Gjertsen BT (2020) Szwed M, Torgersen ML, Kumari RV, Tyrosine kinase inhibitors and inter- Yadava SK, Pust S, Iversen TG, Skot- feron-α increase tunneling nanotube land T, Giri J, Sandvig K (2020) (TNT) formation and cell adhesion Biological response and cytotoxicity in chronic myeloid leukemia (CML) induced by lipid nanocapsules cell lines J Nanobiotechnology, 18 (1), 5 FASEB J 34(3), 3773-3791 Sæbøe-Larssen S, Sioud M (2020) Peng W, de Bruijn HS, Ten Hagen TLM, Improving Dendritic Cell Cancer Berg K, Roodenburg JLN, van Dam Vaccine Potency Using RNA Inter- GM, Witjes MJH, Robinson DJ (2020) ference In-Vivo Optical Monitoring of the Methods Mol Biol, 2115, 249-258 Efficacy of Epidermal Growth Factor

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