Annual Report 2015 From disease mechanisms to clinical practice Contents
Overview by the Director 04
NCMM History in brief 06
NCMM Research NCMM Group Leaders 08 Group Taskén – Signaling Networks in Health and Disease 10 Group Mills – Prostate Cancer 16 Group Morth – Membrane Transport 22 Group Hurtado – Breast Cancer 26 Group Staerk – Stem Cells 30
Research Collaboration with OUS 34
From Disease Mechanisms to Clinical Practice 36
NCMM Associate Investigators 38
Research Highlights 49
NCMM Events 52
King Olav Vs prize 54
NCMM Network Meeting 56
NCMM PhD dissertations 58
NCMM Board 62
Scientific Advisory Board 64
NCMM Funding 66
NCMM-Affiliated Publications and News Items 68
Personnel 74
2 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 3 development, translational medicine strategies April 2016 Overview by the Director and infrastructure. On the European and international arenas, NCMM investigators enjoy numerous Dear friends, colleagues and supporters of NCMM, collaborations across the world (more than 40 international collaborations reported). Research interactions with the three other nodes in the Kjetil Taskén Nordic EMBL Partnership and the EMBL are also Director of NCMM increasing rapidly. Implementation at NCMM of the practices of the parent EMBL in recruitment I am proud to present the 2015 Annual Report NCMM Group Leaders are all established with and rotation of staff at all levels also offers the from NCMM, which summarizes the activities in adjunct appointments in clinical or para- opportunity of recruiting top talent at all levels the 6th full year of operations at NCMM. While clinical departments at Oslo University Hospital on an international arena. NCMM during the first five-year period was (OUH). This involves increasing interactions building up and grew rapidly in terms of mass and and collaborations with Departments of FUTURE PROMISE production, 2015 marked the start of the second Infectious Diseases, Hematology and Institutes As NCMM now has started its second 5-year 5-year period of operations. As described below of Experimental Medicine and Cancer Research, operational period the Centre is at steady state NCMM now presents as a more mature Centre at illustrating the breadth of application and and probably as stable and established as is steady-state, where groups capitalize on projects, extension of the molecular medicine research possible with this model. We are expecting the work and investments initiated earlier and going on in NCMM. Furthermore, NCMM has next 2-3 years should bring significant scientific where well-established and successful groups close links with the Biotechnology Centre as well output from PIs harvesting from strategies set rotate out while new groups are being recruited as additional collaborations across Norway. In out in their first 5-year appointment period. to start new areas of research. This strategy of fact, NCMM group leaders report more than 45 Gradually, we also now see that NCMM groups continuous development of NCMM holds great national collaborations. The experience after 3-5 rotate, as the Nagelhus group moved out at promise also for the future and should allow years with these affiliations is that they facilitate the end of 2014 and the Mills group is now NCMM researchers to keep abreast in the area of clinical collaborations, give group leaders better phasing out since Dr. Ian Mills took up a faculty molecular medicine and translational research. access to patient materials, biobanks and clinical appointment at Queens University Belfast from trials and are crucial to facilitate translational 2015. These and coming rotations will involve research. a second wave of new recruitments and RECENT PROGRESS - Review of 2015 NCMM already recruited a group in SCIENCE AND PUBLICATION OUTPUT A network of NCMM Associate Investigators was bioinformatics from 2016 to be headed by NCMM PIs reported around 50 NCMM-affiliated established in 2010 when the first outstanding Dr. Anthony Mathelier starting in May of papers published in 2015 and the first quarter researchers and key research groups working 2016. of 2016, including papers in Nature Genetics, J. across Norway were appointed Associated Clin Oncol., EMBO Molecular Medicine, Elife and Investigators (AIs). These appointments, subject The Faculty of Medicine hosts NCMM other journals. NCMM investigators have also to application and evaluation by a Selection from 2015 and cooperates closely with filed patents, have started new commercialization Committee, are based on scientific excellence the Faculty of Mathematics and Science projects and report a number of appearances in and translational merit as well as added value in this endeavor, which has also offered popular media. The breadth and depth of the and compatibility with the NCMM mission. new opportunities, both strategically research that now goes on in NCMM is very The network was extended in 2011 and 2014 by with the two Faculties and with more exciting and spans from molecular mechanisms the appointment of additional new members. alignment and potential for synergies regulating normal physiology and contributing Collaborations with this group have been at all levels. to disease to prognostic studies, looking at boosted by joint meetings and by a seed money association of disease markers and clinical program initiated by the NCMM Board to foster In summary, the Nordic EMBL outcome as well as involvement in clinical collaborative projects. In 2015 NCMM called for Partnership in Molecular Medicine intervention trials. selection of new Associate Investigators in an holds great promise for collaboration open call and selected 13 AIs (re-appointed and and joining forces by drawing on each TRANSLATIONAL RESEARCH newly appointed). NCMM has also initiated a other’s strengths. Lastly, as a national As of Q1 2016 NCMM PIs lists some 25 Young Associate Investigator (YAI) program and center for molecular medicine with observational or interventional clinical studies the first two NCMM YAIs were appointed at the responsibility to build networks in the areas of therapy and disease mechanisms University of Tromsø in 2014. In an open call in and facilitate translational research, as well as in the molecular markers, diagnostics 2015, seven new YAIs were appointed bringing NCMM with its Network of NCMM and monitoring areas. The extent of clinical the total associate investigator network of AIs Associate Investigators is a tool that collaborations and activity with translational and YAIs to 22 members. The NCMM network can be used to foster collaboration and clinical studies thus continues steadily at a meeting in January of 2016 gathered NCMM and excellence in research which high level. PIs, new AIs and YAIs and other stakeholders partners across Norway are invited to to an interactive programme of talks and take ownership to and utilize. COLLABORATION AND NETWORKS active discussions of scientific leadership, As a part of the focus on translational research, funding strategies, research policies, career
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The Centre for Molecular Medicine Norway to consolidate the success already achieved, to (NCMM) is part of the Nordic EMBL Partnership ensure further growth and to build up strategic for Molecular Medicine which was established in areas in order to come above critical mass. 2007 as a joint venture (2008-2012) between the Funding was therefore committed for a second European Molecular Biology Laboratory (EMBL) five-year period (2015-2019) from the consortium and the Universities of Helsinki, Oslo and Umeå. partners. A Danish node (Dandrite) joined the Partnership in 2013. The Partnership is dedicated to the INCOME AND EXPENSES growing field of Life Sciences that investigates The NCMM core funding in the second five-year the molecular basis of disease and explores period (2015-2019) is 31 million Norwegian kroner molecular and genetically based treatments. It (mNOK) (approximately 3.8 mEUR) per year from capitalizes on regional, complementary strengths the 3 consortia partners UiO, Research Council in the Nordic countries and each of the four of Norway and Health SouthEast. Furthermore, partner nodes brings in a unique set of expertise, overhead and production-based income comes skills and facilities encompassing EMBL’s in addition. In 2015, NCMM spent 26 mNOK recognized research strengths in the areas of which was less than budgeted due to rotation molecular, cellular and developmental biology, of groups and lags in hiring. For 2016, NCMM bioinformatics and structural biology. Altogether, plans to spend 37 mNOK, including transferred the Nordic EMBL Partnership constitutes a funds (see overview of NCMM finances). For the coordinated Nordic infrastructure for enhancing period 2017-2019 we stipulate the NCMM annual The overall objective of NCMM is to conduct molecular medicine scientific findings through a core budget expenses to be in the order of 35-38 translational research pipeline, putting scientific mNOK (2015-value) with the present level of cutting edge research in molecular medicine discoveries into clinical use in an efficient way activity and additional income from overhead and equipping the partners to tackle some of the and production-based income and including most challenging problems of biomedicine. transferred funds. and facilitate translation of discoveries in
NCMM was formally inaugurated as a joint NCMM extramural funding in the form of grants basic medical research into clinical practice. venture between the University of Oslo (UiO), to the group leaders and other competitive as host, the Research Council of Norway (RCN) funding has increased steadily from 7 mNOK in and Health Region South East (HSE) at the end of 2010 to 35 mNOK in 2013. In 2014 NCMM reached 2008. The overall objective of NCMM is to conduct 43 mNOK in annual grants and was maintained cutting edge research in molecular medicine and at this level with 42 mNOK in 2015 although we facilitate translation of discoveries in basic medical stipulate a drop to approx. 35 mNOK in 2016 due to research into clinical practice. NCMM focusses rotation of groups. The external funding includes particularly on disease mechanisms where grants from the Research Council of Norway, Norway has clear strengths and investigates Norwegian Cancer Society, Health SouthEast, mechanisms of non-communicable diseases European Commission, competitive grants at such as cancer, cardiovascular and CNS-related UiO and private foundations and organizations disease and immune disorders. NCMM develops such as the Lundbeck Foundation, Novo Nordic and adapts technologies for personalized medical Foundation, KG Jebsen Centres, Movember and applications and has unravelled new diagnostic others. methods and drug targets. The Nordic nodes within the EMBL Nordic NCMM had its first full operational year in 2010 Partnership are also supported by Nordforsk as a and a midterm evaluation carried out by an Nordic Network of National Centres of Excellence. external, international committee took place in This network “Nordic Molecular Medicine 2013. The committee recommended that NCMM Network” (NMMN) promotes collaboration should be continued for a second five-year and exchange between FIMM, NCMM, MIMS, period and that funding should be strengthened Dandrite and EMBL.
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interested in transcriptional and regulatory From left: J. Preben Morth, networks in prostate cancer and aims to Antoni Hurtado, Kjetil Taskén, better define the interplay between membrane Judith Staerk and Ian Mills trafficking, metabolism and transcription in NCMM Group Leaders prostate cancer as proteins in regulatory hubs for these processes have potential value as cancer biomarkers and therapeutic targets. Mills accepted a position at Queens University of Belfast in 2015 and will leave NCMM in June 2016.
Dr. Jens Preben Morth was trained in structural biology at the EMBL Outstation in Hamburg and was recruited from Aarhus University to NCMM in October 2010. His research is in the area of structure and function of membrane transporters. Morth has also started a new program on pH regulation and structure function studies on bicarbonate transporters. His research has relevance to cardiology, neurobiology and kidney diseases. Morth’s appointment as group leader was evaluated in 2015 and his position was renewed for a second five-year period (2015- 2019).
Dr. Toni Hurtado did his PhD at the Vall Hebron Hospital in Barcelona and his postdoc at Cambridge Research Institute, University of Cambridge. Hurtado started as a Group Leader at NCMM in 2011 and his research is focused on breast cancer, estrogen sensitivity and the role of co-factors in transcriptional networks.
Dr. Judith Staerk trained at the Ludwig Institute for Cancer Research and Catholic University in Brussels, did her postdoc at Whitehead Institute, MIT working with stem cells and started in her NCMM Group Leader appointment in 2012. Her research is focused on stem cell biology, hematopoetic stem cells and myeodysplastic and myeloproliferative syndromes.
Dr. Anthony Mathelier is a computer scientist by background who did his PhD at the Pierre and Marie Curie University, Paris. Mathelier was recruited from the University of British Columbia, Vancouver, Canada and will join NCMM from May 2016. He aims at developing cutting-edge bioinformatics tools with immediate application to real-life biological problems and his research group will focus on gene expression In the period 2009-11 NCMM hired five new young Recently, NCMM recruited a new group leader in was appointed Director from January 2011 and regulation and the mechanisms by which it can group leaders. In addition, appointed NCMM bioinformatics, Anthony Mathelier, and he will reappointed for a second 5-year period from 2016. be disrupted in human diseases such as cancer. Director Kjetil Taskén is leading a research group start in May 2016. Furthermore, NCMM is in the His research is in the area of cell signaling and at NCMM. Group Leader Erlend Nagelhus was process of recruiting another group leader that immunomodulation with application in immune The research groups at NCMM are presented in appointed Professor of Medicine (Physiology) will also function as Assistant Director. diseases, inflammation and tumor immunology. more detail in the following pages. at the University of Oslo in 2013 and therefore rotated out from NCMM when his first five-year Professor Kjetil Taskén, identified by the Dr. Ian G. Mills was recruited from Cambridge contract ended in November 2014. He has now Research Council as one the founding members Research Institute, Cancer Research UK, been appointed NCMM Associate Investigator. of NCMM, served as Interim Director 2008-10, University of Cambridge in 2010. Mills is
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Kjetil Taskén
Signaling networks in health and disease
One main focus is to understand why the of this understanding the group maps signaling immune system sometimes turns off its ability pathways, identifies targets, develops tools to recognize and kill cells in an expanding to perturb signaling (peptidomimetics, small malignant tumour. We aim to understand how molecular compounds) and provides “proof-of- tumours develop immune evasion strategies, principle” experiments using specific disease what mechanisms operate in different cancers models. and how we can perturb such immune-inhibitory signals to boost anti-tumour immunity and assist The Taskén group employs a breadth of other cancer immunotherapies. techniques in bioinformatics, proteomics, phospho-flow analysis, chemical biology high- We are starting work with cancer drug throughput screening assays and genetic tools in sensitivity screening on patient samples looking order to screen new targets for in vitro and in vivo for efficacious compounds and drug synergies function. In order to isolate signalling complexes on an individual basis, ultimately aiming to from a variety of targets, including T cells, assist clinical decisions in precision oncology cardiomyocytes, adipocytes and organelles such and hematology. Other activities focus on the as lipid droplets and mitochondria, a chemical role of the cAMP second messenger system genomics approach is used in combination and other signal networks in the regulation with phospho-proteomics to understand of cellular function and its involvement in spatiotemporal dynamics of phosphorylation in disease mechanisms in inflammation as well anchored signaling complexes. Chemical biology as in infectious, metabolic and cardiovascular screenings identify small molecular compounds diseases. for our research. Furthermore, phospho-flow cytometry using fluorescent cell barcoding allows Description of the Group’s Research mapping of complex signal networks, assessing The group aims to understand complex how inhibitory signals feed in and examining intracellular signaling networks and how such how small molecules perturb such signal networks require anchoring and localization networks. Our recent technology developments through A kinase anchoring proteins (AKAPs) or now also allow flow-based signalling analyses other scaffold proteins. The group investigates of adherent cells and high-throughput chemical how these signaling networks mediate hormonally biology screening by flow cytometry. regulated physiological and pathophysiological processes. In the immune system we investigate The group studies cAMP immunomodulation cAMP- and regulatory T cell-mediated immune- and involvement of regulatory T cells in modulation with application in immune diseases, HIV, mouse AIDS and various cancers where inflammation and tumor immunology. In pursuit tumour immunology is of significance. Projects
10 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 11 RESEARCH GROUPS KJETIL TASKÉN “The group aims to understand complex intracellular signaling networks”
include studies of regulatory T cells and anti- • Raslan, Z., Magwenzi, S., Aburima, A., Taskén, Line, P.D., Labori, K.J., Wiedsvang, G., Taskén, A first report from our cancer drug sensitivity tumour immune responses in colorectal cancer, K., Naseem, K.M. (2015) Targeting of Type I Pro- K., Aandahl, E.M. Regulatory T cells that co-ex- screening approaches in chronic lymphatic pancreatic cancer, cholangiocarcinoma and tein Kinase A to lipid rafts is required for plate- press RORγt and FOXP3 are pro-inflammatory and leukemia using phospho-flow cytometry to ovarian carcinoma. In addition, cancer and let inhibition by the cAMP-signaling pathway. J. immunosuppressive and expand in human pan- assess effect of targeted therapy drugs is also immune cell signalling analyses are being Tromb. Haemostasis, 13:1721-34. creatic cancer. Oncoimmunol. In press. now out: performed by phospho-flow cytometry to find bio • Landskron, J., Taskén, K. (2016) Phosphopro- • Chelappa, S., Hugenschmidt, H., Hagness, M., • Parente-Ribes, A.*, Skånland, S.S.*, Bürgler, S.*, signatures. A recent interest is now to rig drug tein detection by high-throughput flow cytometry. Line, P.D., Labori, K.J., Wiedsvang, G., Taskén, Os, A, Wang, D., Bogen, B., Tjønnfjord, G.E., sensitivity screens to explore the possibility to Methods in Molecular Biology,1355: 275-90. K., Aandahl, E.M. CD8+ T cells that co-express Taskén, K.$,#, Munthe, L.A. $,# Spleen tyrosine ki- assist treatment choices in individualized cancer RORγt+ and T-bet are functionally impaired and nase inhibitors block CD40L induced proliferation therapy, particularly looking at haematological We have looked at the role of regulatory T cells expand in patients with distal bile duct cancer. of chronic lymphocytic leukemia cells. Hemato- malignancies. Furthermore, systems biology in tuberculosis and HIV, their activation status Resubmitted. logica, in press (*,$equal contributions, #corre- analyses are applied on the phospho-flow data as evident from FoxP3 staining and levels of • Chelappa, S., Aandahl, E.M., Taskén, K. Can- sponding authors). from single cell signalling as well as from mixed CD147 and the effect of perturbing regulatory T cer immunity and immune evasion mechanisms. cell populations with Treg immunosuppression. cell activation by MEK inhibitors in collaboration In Biomarkers of the Tumor Microenviron- Current research also includes examination with the Department of Infectious Diseases, Oslo ment: Basic Studies and Practical Applications of cAMP and beta-adrenergic signalling in The improved understanding of signaling University Hospital (OUH). (Eds. Lars A. Akslen and Randolph S. Watnic, the heart and in adipocytes with relevance to networks can be applied to many disease states, • Lieske, N.V., Tonby, K., Kvale, D., Dyrhol-Riise, Springer). Accepted for publication. cardiovascular and metabolic diseases, including including immune-deficiencies, inflammatory A.M., Taskén, K. (2015) Targeting disease-specif- studies of an AKAP18 signal complex regulating disorders and cancers and may promote the ic regulatory T cells in chronic infectious diseases We earlier demonstrated that regulatory T cells Ca2+ re-uptake in sarcoplasmic reticulum and development of highly specific pharmaceuticals with MEK/ERK signaling pathway inhibitors. PLoS and prostaglandin E2 (PGE2) suppresses anti- contractility (Calejo, Østensen). Ongoing work that maximize their therapeutic value, while One, 10: e0141903, pp 1-19. tumour immune responses in colorectal cancer includes chemical biology high-throughput minimizing unwanted side-effects. • Stiksrud, B., Lorvik, K.B., Kvale, D., Mollnes, (Yaqub et al, Cancer Immunol. Immunother. 2008; screening, subsequent characterization of hits T.E., Ueland, P.M., Trøseid, M., Taskén, K. Brudvik et al, . Cancer Immunol. Immunother. as well as proof-of-concept studies in animals Achievements in 2015 Dyrhol-Riise, A.M. Plasma Interferon-inducible 2012). These observations add to reports that in vivo both in normal physiology and in
We have studied signalling in immune cells, Protein10 Levels, T-cell Activation and Regulation PGE2 stimulates tumor growth and angiogenesis ischemia-reperfusion injury. Another ongoing particularly how regulatory and effector T are Increased in HIV Immunological Non-Respond- in colorectal cancer. While COX inhibitors and project investigates the function of Opa1 in cell signalling is reciprocally affected during ers. J. AIDS in press, acetylsalicylic acid may be beneficial to prevent regulating cAMP signalling in lipid droplets and suppression and in collaborative papers how primary colorectal cancer, our findings on the mitochondria (Rogne, Mylonaku, Dinescu, Chu). adaptive NK cell signalling involves CD2. We have characterized regulatory T cells inhibitory effect of PGE2 on anti-tumor immunity • Calejo, A.I., Taskén, K. (2015) Targeting pro- Furthermore, we have examined how regulation in various cancer types and assessed their led us to hypothesize that secondary prevention tein-protein interactions in complexes organized of platelet functions depend on anchored cAMP involvement in tumor immune evasion. with acetylsalicylic acid may give even further by A kinase anchoring proteins. Front. Pharma- signalling pathways. • Landskron, J., Helland, Ø., Torgersen, K.M., benefit. This appears to hold true in a registry col., 6:192, pp1-13. • Chelappa, S., Lieske, N.V., Hagness, M., Line, Aandahl, E.M., Gjertsen, B.T. Bjørge, L., study with data on more than 23,000 patients P.D., Taskén, K.,#Aandahl, E.M.# (2016) Activa- Taskén, K. (2015) Activated regulatory and mem- from the Cancer Registry of Norway coupled External funding (brief) tion status of human regulatory T cells controls ory T-cells accumulate in malignant ascites from with data from the Norwegian Prescription In addition to support from NCMM and the TCR signaling and susceptibility to suppression ovarian carcinoma patients. Cancer Immunol. Database. We now plan a clinical intervention Biotechnology Centre of Oslo, the Taskén in CD4+ T cells. J. Leukocyte Biol., in press in Immunother., 64: 337-47. trial to assess this finding in a randomized and group has in 2015 had funding from a variety “Leading Edge Research” section. (#corre- • Santegoets, S.J.A.M., Dijkgraaf, E.M., Batta- placebo-controlled setting. of sources including the Research Council of sponding authors) glia, A., Beckhove, P., Britten, C.M., Gallimore, • Bains, S.J., Mahic, M., Myklebust, T.Å., Småst- Norway (FRIPRO, Biotek2021), the Norwegian • Liu, L., Landskron, J., Ask, E.H., Enqvist, M., A., Gouttefangeas, C., de Gruijl, T.D., Koenen, uen, M.C., Yaqub, S., Dørum, L.M., Bjørn- Cancer Society, Health South-East Regional Sohlberg, M., Traherne, J., Hammer, Q., Good- H.J.P.M., Scheffold, A., Shevach, E.M., Staats, beth, B.A., Møller, B., Brudvik, K.W., Taskén, Health Authority, the EU 7th Framework and ridge, J., Larsson, S., Jayaraman, Oei, V.Y.S., J., Taskén, K., Whiteside, T.L., Kroep, J.R., Wel- K. Aspirin as Secondary Prevention in Patients ESFRI programmes, Nordforsk, Novo Nordic Schaffer, M., Taskén, K., Ljunggren, H.-G., ters, M.J.P., van der Burg, S.H. (2015) Monitor- with Colorectal Cancer - An Unselected Popula- Foundation as well as from the K.G. Jebsen Romagnani, C., Trowsdale, J., Malmberg, K.- ing regulatory T cells in clinical samples: consen- tion-Based Study. J. Clin Oncol., in press. Foundation that is funding two translational J., Béziat, V. (2016) Critical role of CD2 co-stim- sus on an essential marker set and gating strategy research Centres with Taskén as partner, The ulation in adaptive NK cell responses revealed in for regulatory T cell analysis by flow cytometry. K.G. Jebsen Inflammation Research Centre and NKG2C-deficient humans. Cell Reports, 15: 1–12, Cancer Immunol. Immunother., 64:1271-86. K.G. Jebsen Centre for Immunotherapy. May 10, 2016. • Chelappa, S., Hugenschmidt, H., Hagness, M.,
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Group members Collaborations Group members (during 2015 and first quarter of We collaborate with more than 20 international 2016): partners, in 2015 most actively with the groups of Professor John D. Scott, University of Research Scientists: Washington, Seattle; Professor Albert Heck, The Einar Martin Aandahl Netherlands Proteomics Centre, Utrecht; Group Johannes Landskron leader Klaus Okkenhaug, Babraham Institute, Sigrid S. Skånland Cambridge, UK; Dr. Guillaume Pidoux, Université Paris Süd; Professor Bodo Grimbacher, Freiburg Postdoctoral fellows: University; and Dr. Krister Wennerberg, FIMM, Ana Isabel Costa Calejo Helsinki, Finland. Dinh-Toi Chu (from Oct. 2015) Sorina Dinescu (from Jan to May and August to Nationally the group has in 2015 collaborates Dec 2015) with Group Leaders Judith Staerk, J. Preben, “One main focus is to understand why Lena Eroukhmanoff (until May 2015) Morth and Camila Esguerra Biotechnology Morten Hagness (until Sept 2015) Centre / NCMM and Professors Philippe Collas, the immune system sometimes turns off Guro Mørk Johnsen (until March 2015) Jo Klaveness, Arnoldo Frigessi, Bernd Thiede, Anna Mari Lone University of Oslo; Professors Dag Kvale and Anne its ability to recognize and kill cells in an Kristina Berg Lorvik Ma Dyrhol-Riise, Dept. of Infectious Diseases, Maria-Niki Mylanokou (until May 2016) Senior Consultants Bjørn Atle Bjørnbeth and Deepak Balaji Thimiri Govinda Raj Sheraz Yaqub, Gastrosurgical Dept., Professor expanding malignant tumour” Vanessa L. Wehbi Ivar Sjaastad, Institute of Experimental Medical Research, Professor Guttorm Haraldsen, Dept. PhD Fellows: of Pathology, Professor Ludvig Munthe, Institute Simer Jit Bains (until April 2015) of Immunology, Professor Geir E. Tjønnfjord Aleksandra Đukić Dept. of Hematology Professor Pål Aukrust Stalin C. Gunasekaran Dr. Arne Yndestad, Professor Bente Halvorsen Nora V. Lieske (until August 2015) and Professor Tom Hemming Karlsen; Inst. of Kristine Moltu (until August 2015) Internal Medicine Research, Professors Johanna Ellen Østensen Olweus and Professor Kalle Malmberg, Dept of Immunology, Inst. for Cancer Res., Dr. Jorrit MSc students: Enserink, Dept. of Microbiology and Professor Ida Kristin Myhrvold (until May 2016) Annetine Staff, Dept Ob-Gyn, Oslo University Marthe Jøntvedt Jørgensen (from January 2016) Hospital; Professor James B. Lorens, University of Bergen, Professors Bjørn Tore Gjertsen, Administrative Officer: Helga Salvesen and Senior Consultant Line Berit Barkley Bjørge, Haukeland University Hospital, Bergen; Professor Anders Sundan, NTNU and Senior Scientific Officers: Researcher Geir Klinkenberg, SINTEF. Marianne Enger (from February 2016) Jorun Solheim (until April 2016) Martine Schrøder (from February 2016) Gladys Tjørhom
Chemical Biology Platform: Anne Jorunn Stokka, head Paul R. Berg (from February 2016) Eirin Solberg (from January 2016) David W. McClymont (Until Nov 2015)
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Ian G. Mills
Prostate Cancer Research Group
Prostate cancer is a high-incidence cancer in men of lethal castrate-resistant disease and that with progression to metastatic disease occurring the activity of a key transcription factor in around 20-30% of detected cases. Major in prostate cancer, the androgen receptor translational challenges include the development (AR), is modified by the expression of other of biomarkers able to predict progression at oncogenic transcription factors with a focus the time of diagnosis and treatment response/ here principally on c-Myc. Additionally, we failure as well the need to develop more effective have found that regions of open chromatin treatment strategies. Our strategy for addressing are hotspots for prostate cancer risk loci. this has been to explore how transcription factors and chromatin change in transformed 2. Autophagy: Autophagy (‘self-eating’) is a cells and how the gene networks that they key stress response that can have pro-sur- regulate map back to clinical expression profiles. vival or pro-apoptotic properties in cancer From the resultant gene networks and pathway cells depending on the context and trigger. enrichments we have identified biological Whilst this has been recognised by groups processes that we believe are important to worldwide, the desire to achieve clinical regulate progression and treatment response translational endpoints through the study and have gone on to study these functionally of autophagy has led to the over-interpre- and, with clinical collaborators, to evaluate tation of assays and autophagic markers. A candidate biomarkers. From this work the main key contribution that we are making in this biological focus of the group is on stress response area is to carefully dissect whether auto- signalling sub-divided broadly into glycosylation phagic markers are also necessary to drive and the unfolded protein response/autophagy. In the functional biology of the autophagic particular, we are focussing on how genes that process. We are addressing this by devel- function in these processes confer resistance to oping and qualifying autophagic assays and therapeutic and oncogenic stress and how they then testing the impact of genetic targeting can be targeted therapeutically. of autophagic factors. With that knowledge in place the program will then move on to Description of the Group’s Research explore how these factors affect response to 1. Chromatin biology and transcription- treatments such as anti-androgens. al regulation: Predominantly we employ high-throughput sequencing and transcript 3. Glycosylation: Glycosylation is a bridge be- profiling to map genome-wide changes in tween metabolic changes, protein folding transcription factor recruitment and chro- capacity and in turn the stability and activ- matin compaction in cell-lines and clinical ity of oncogenes. We realised the potential samples. Using these approaches we have importance of glycosylation early in the de- found that chromatin opening is a hallmark velopment of our research program based
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on clinical profiling and mapping of target • Myc drives the expression of enzymes in genes for the androgen receptor and other the de novo purine biosynthesis pathway transcription factors. In particular, we have and inhibitors of this pathway disassemble been exploring how a pathway called the nucleoli and enhance response to anti-andro- hexosamine biosynthesis pathway affects gens. This study identified genes that were the stability of c-Myc and other oncogenes Myc-dependent, overexpressed in prostate and the response to activators of the unfold- cancer, required to maintain stress resistance ed protein response. This pathway is fuelled and encoding enzymes that are drugable by by metabolites drawn from all of the core repurposing clinical approved drugs. En- metabolic processes in the cell to form a zymes in the de novo purine biosynthesis single amino-sugar-nucleotide conjugate – fulfil these criteria and the study creates the UDP-GlcNAc. Whilst heightened activity of potential for further pre-clinical and clinical this pathway is required to sustain protein evaluation of drugs targeting this pathway to tential of pancreatic cancer cells following Glycosylation folding in untransformed secretory cells, the improve response to next-generation anti-an- long-term 5-FU treatment. This study identi- This theme has been driven forward by Harri same pathway can also confer resistance to drogens. fied L1CAM as a mediator of a pro-metastatic Itkonen. environmental stress and consequently the biology in 5-fluorouracil resistant pancreatic expression and activity of enzymes in the Barfeld SJ, Fazli L, Persson M, Marjavaara L, Ur- cancer cells. We identified the target from • UDP-N-acetylglucosamine pyrophosphoryl- pathway and fuelled by the pathway are re- banucci A, Kaukoniemi KM, Rennie PS, Ceder Y, transcription profiles. ase 1 (UAP1), an enzyme in the hexosamine tained and amplified in cancer cells. Chabes A, Visakorpi T, Mills IG (2015) Myc-depen- biosynthesis pathway, inhibits apoptotic dent purine biosynthesis affects nucleolar stress Lund K, Dembinski JL, Solberg N, Urbanucci A, responses to drugs that induce protein fold- 4. Biomarkers: Since prostate cancer progress- and therapy response in prostate cancer. Oncotar- Mills IG, Krauss S (2015) Slug-dependent upreg- ing stress. We have previously reported that es in a subset of diagnosed cases to a lethal get 6: 12587-602 ulation of L1CAM is responsible for the increased the hexosamine biosynthesis pathway is an metastatic disease and the current bio- invasion potential of pancreatic cancer cells fol- effector for metabolic feedback on oncogenic marker, prostate specific-antigen (PSA), is Other collaborations: lowing long-term 5-FU treatment. PLoS One 10: stability and signalling in prostate cancer and relatively ubiquitous, there is a significant e0123684 is AR-dependent. Here we show that one en- need for biomarkers that flag heightened • Divergent androgen regulation of unfolded zyme in this pathway modifies the response risk of disease progression. We are evalu- protein response pathways drives prostate Autophagy of prostate cancer cells to drugs that impose ating transcripts and proteins as candidate cancer. This study defined the IRE1-XBP1 The Autophagy team led by Dr. Nikolai Engedal folding stress on cells. biomarkers focussing predominantly on arm of the unfolded protein response as an (Senior Scientist) and Professor Per Seglen ‘liquid biopsy’ (urine, blood and circulat- AR-driven arm required to support tumori- (Guest researcher) has continued to make sig- Itkonen HM, Engedal N, Babaie E, Luhr M, Guldvik ing tumour cells). Amongst these sample genesis as well as indicating that the PERK- nificant progress in dissecting the contribution IJ, Minner S, Hohloch J, Tsourlakis MC, Schlomm types we have so far made most progress ATF4 arm is antagonised. of LC3 and GABARAPs to autophagy and the re- T, Mills IG (2015) UAP1 is overexpressed in pros- in evaluating markers in blood samples. lationship between cargo sequestration and fu- tate cancer and is protective against inhibitors of Since it typically takes 5-10 years from di- Sheng X, Arnoldussen YJ, Storm M, Tesikova M, sion of autophagic structures with the lysosome. N-linked glycosylation. Oncogene 34: 3744-50 agnosis to disease progression, blood sam- Nenseth HZ, Zhao S, Fazli L, Rennie P, Risberg B, Some highlights in 2015 have included: ples represent a sample type that currently Waehre H, Danielsen H, Mills IG, Jin Y, Hotamis- • Targeting OGlcNAc transferase (OGT) creates has the longest follow-up time having been ligil G, Saatcioglu F (2015) Divergent androgen • Evidence that bulk autophagic sequestration an opportunity for repurposing clinically biobanked. By contrast urine sample col- regulation of unfolded protein response pathways does not require LC3 but is dependent on approved metabolic inhibitors. A key finding lections are still relatively recent and there drives prostate cancer. EMBO Mol Med 7: 788-801 GABARAPs. was the targeting OGT, an enzyme we have remains controversy over the best detection previously found to be important for the sta- platform for circulating tumour cells. The • The androgen receptor controls expression Szalai P, Hagen LK, Saetre F, Luhr M, Sponheim M, bility and activity of oncogenic transcription biomarkers that we have been testing have of the cancer-associated sTn antigen and cell Overbye A, Mills IG, Seglen PO, and Engedal N. factors, enhances the cytotoxic response to arisen from three sources. Transcript bio- adhesion through induction of ST6GalNAc1 Autophagic bulk sequestration of cytosolic cargo is mitochondrial inhibitors and to inhibitors of markers have either been derived from our in prostate cancer. This study identified an independent of LC3, but requires GABARAPs. Exp alanine metabolism. pre-clinical studies or through collaboration enzyme required for sialylation as an AR-de- Cell Res. 2015;333(1):21-38. with international research consortia. Pro- pendent and regulating cell adhesion in Itkonen HM, Gorad SS, Duveau DY, Martin SE, tein biomarkers have arisen from proteomic prostate cancer. • Further refinements of functional assays for Barkovskaya A, Bathen TF, Moestue SA, and Mills profiling of Janus Serum Bank samples and autophagic cargo sequestration to enable IG. Inhibition of O-GlcNAc transferase activity downstream validation in samples obtained Munkley J, Oltean S, Vodak D, Wilson BT, Liver- their adoption across the research commu- reprograms prostate cancer cell metabolism. On- from other Nordic and UK sample collec- more KE, Zhou Y, Star E, Floros VI, Johannessen B, nity. cotarget 2016 [Epub ahead of print]. doi: 10.18632/ tions through collaboration. Knight B, McCullagh P, McGrath J, Crundwell M, oncotarget.7039 Skotheim RI, Robson CN, Leung HY, Harries LW, Seglen PO, Luhr M, Mills IG, Saetre F, Szalai P, and Achievements in 2015 Rajan P, Mills IG, Elliott DJ (2015) The androgen Engedal N. Macroautophagic cargo sequestration Biomarkers and genetic risk factors Chromatin biology and transcriptional regulation receptor controls expression of the cancer-associ- assays. Methods. 2015;75(25-36. This theme has been driven forward by Ingrid This work has been driven forward by Alfonso ated sTn antigen and cell adhesion through induc- Guldvik and Verena Zuber. The predominant fo- Urbanucci and Stefan Barfeld. tion of ST6GalNAc1 in prostate cancer. Oncotarget Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, cus here has been on further identification and 6: 34358-74 Abeliovich H, Acevedo Arozena A, Adachi H, Adams validation of candidate prognostic and predic- • PhD defense – Stefan Barfeld – ‘The transcrip- CM, Adams PD, Adeli K, et al. Guidelines for the use tive prostate cancer biomarkers. Protein-based tional role of c-Myc in prostate cancer’ • Slug-dependent upregulation of L1CAM is and interpretation of assays for monitoring biomarkers in blood have reached the PCT filing responsible for the increased invasion po- autophagy (3rd edition). Autophagy. 2016;12(1):1-222. stage (patent) – ‘PROSTATE CANCER MARKERS
18 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 19 RESEARCH GROUPS IAN G. MILLS
AND USES THEREOF’ - PCT/US16/12194. Professors Fredrik Wiklund and Henrik Gron- berg (Karolinska Institute) – blood-based bio- In collaboration with Professor Ole Andreassen markers (Oslo University Hospitals) and Professor Tere Professor Fahri Saatcioglu (University of Oslo) Landi (National Cancer Institutes) we have iden- – Unfolded protein response and blood-based tified a new genetic cancer risk locus for lung biomarkers cancer by undertaking a pleiotropy analysis ver- Dr. Bernd Thiede (University of Oslo) – clinical sus blood lipid traits. proteomics Professor David Neal (Universities of Oxford Pleiotropic analysis of lung cancer and blood tri- and Cambridge) – blood-based biomarkers glycerides identifies a shared genetic locus – Zuber Professor Suzanne Walker (Harvard Medical et al., In revision School) – OGlcNac transferase inhibitors Professor Thorsten Schlomm and Dr. Sarah Other genetic pleiotropy paper in 2015: Andreassen Minner (Hamburg University Medical School/ OA, Desikan RS, Wang Y, Thompson WK, Schork Eppendorff Hospital) – urine and tissue-based AJ, Zuber V, Doncheva NT, Ellinghaus E, Albrecht biomarkers M, Mattingsdal M, et al. Abundant genetic overlap Professor Kristin Tasken (Oslo University Hos- between blood lipids and immune-mediated diseases pitals) and the Norwegian Biomarker Consor- indicates shared molecular genetic mechanisms. tium – prostate cancer biomarkers PLoS One. 2015;10(4):e0123057. Professor Tere Landi (National Cancer Insti- tutes) – Lung cancer genetic risk factors PRAC- “The goal of the group is to understand TICAL and ELLIPSE Consortia (UK and global) External Funding – Prostate cancer genetic risk factors the biology of prostate cancer in order to RCN (Young Talent Grant to Nikolai Engedal) Professor Ole Andreassen (NCMM Associate The Norwegian Cancer Society (Per Seglen) Investigator/Oslo University Hospitals) – pleiot- improve detection and treatment” The Nansen Foundation (Nikolai Engedal) ropy and cancer risk loci Lundbeck Foundation PhD Fellowship (Nikolai Jon Bendik-Thue (MyHere) – development of Engedal in collaboration with Poul Nissen, Aar- an app-based risk assessment tool for prostate hus University) cancer. Norwegian Cancer Society/Movember Team Professor Matthias Wilmanns (EMBL Hamburg) Science Award (Mills) – CAMKK2 Helse SørØst postdoc grant (Mills) Dr. Preben Morth (NCMM) – CAMKK2 Norwegian Cancer Society postdoc grant and Dr. Judith Staerk (NCMM) – chromatin alter- running costs (Mills) ations in the haematopoietic lineage Helse SørØst and University Oslo Innovation Dr. Toni Hurtado (NCMM) – chromatin looping Awards (Mills) and alterations in breast and prostate cancers. RCN FRIMEDBIO Program Grant (Mills) Professor Ole Petter Rekvig (NCMM Associate RCN FORNY Innovation Award (Inven2/Mills) Investigator/University of Tromso) – lupus genes as cancer biomarkers and drivers Group Members Professor Poul Nissen (Director of DANDRITE Nikolai Engedal – Senior Scientist and Professor at Aarhus University) – collabo- Professor Per Seglen – Guest Researcher ration with Dr. Nikolai Engedal on the SERCA Ingrid Guldvik – Head Engineer pump and autophagy Frank Saetre – Principal Engineer Professor Angelo DeMarzo and Professor Srini- Harri Itkonen – Postdoc vasan Yegnasubramanian (Johns Hopkins Med- Alfonso Urbanucci – Postdoc ical University) – Myc-dependent biomarkers Lisa Gerner – PhD Student and gene networks Paula Szalai – PhD Student (supervisor: Nikolai Engedal). Successfully defended her Masters’ And many, many others who have contributed thesis in summer 2015. in so many ways to the research programs and Morten Luhr – PhD Student (supervisor: Nikolai of course the group itself. Engedal) Stefan Barfeld – PhD student. Thesis defended successfully autumn 2015 Verena Zuber – Began a new postdoc position at EMBL EBI June 2015
Collaborations Dr. Wolfgang Lilleby (Oslo University Hospitals) – biomarkers/Ultimovacs clinical trial
20 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 21 RESEARCH GROUPS
Preben Morth
Membrane Transport Group
The Morth group employs a structural systems The core domain found centrally in the NTD has biology approach to investigate the proteins been crystallized and the structure determined involved in acid-base homeostasis and metal at 4.0 Å resolution. The NTD of NCBE is found to ion transport across the cellular membrane. contain regions of intrinsic protein disorder and A variety of techniques are used in order to these disordered regions are conserved among identify and characterize both soluble and all bicarbonate transporters of the SLC4 family. membrane bound proteins involved in pH The disordered regions coincide with regions regulation. A bioinformatics approach is used to of sequence variation, indicating that although target new proteins and interaction partners of sequence is not conserved, the disorder is. interest. Furthermore, X-ray crystallography and several biophysical methods to obtain structural P-type ATPases in infectious diseases information as well as biochemical techniques The system is strongly dependent on the ion are also used, including activity assays and gradients maintained by the P-type ATPases. fluorescence spectroscopic measurements. The group therefore aims to develop a complete structural model for anion transport and Description of the Group’s Research recognition. Structural analysis of P-type To study the 3D atomic structure of membrane ATPases will continue with focus on the proteins, the group is currently developing prokaryotic Ca2+ ATPases and Mg2+ ATPases. In purification and lipid vesicle reconstitution particular, we are focusing on their function as protocols. The aim is to purify and characterize participants in virulence systems. The systems these membrane proteins. in question originate from Listeria monocytogenes and Salmonella typhimurium, and our work on The bicarbonate transporters translation in infectious diseases like Salmonella Acid-base homeostasis is fundamental to our will bridge the gap between lab bench and clinic. understanding of human physiology and is Our strong focus on developing in vitro assays to essential to cellular function. The main buffering study these particular membrane transporters system found in the human body is based on will allow direct inclusion into the exciting drug bicarbonate. The SLC4 proteins are the main screening platforms in Europe. Furthermore, facilitators of bicarbonate transport across these projects can benefit the broad scientific the plasma membrane, however, not much is community located in Oslo, focusing on known about the structural basis of function infectious diseases. and regulation of these. The N-terminal cytoplasmic domain (NTD) of the sodium- Characterization of supramolecular Tankyrase coupled chloride bicarbonate exchanger (NCBE), complexes implicated in colorectal cancer, found predominantly in the choroid plexus of the using an intrinsically disordered protein as bait brain, has been cloned, expressed and purified. A translational project focusing on identification
22 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 23 RESEARCH GROUPS PREBEN MORTH of large supramolecular complexes implicated catalytic feature common to all hydrolases and in the Wnt pathway was initiated by the is here trapped and visualized for the first time Morth group. We are performing structural (2) . Biophysical and structural interpretation studies of a human ADP-ribosyltransferase of the IHB structure lead to a detection and tankyrase (TNKS), trying to identify novel direct quantification assay of Isatin in blood based on interaction partners by using a proteomics the recombinant enzyme (3). approach in collaboration with Bernd Thiede (BiO). Tankyrases belong to the poly (ADP- 2. Bjerregaard-Andersen, K., Sommer, T., Jensen, ribose) polymerase (PARP) superfamily and are J.K., Jochimsen, B., Etzerodt, M. and Morth, J.P. involved in various cellular functions such as (2014) A proton wire and water channel revealed telomere maintenance, centrosome maturation, in the crystal structure of isatin hydrolase. J. Biol. Wnt signaling, embryonic development and the Chem. 289, 21351-21359 pathogenesis of Cherubism. We are currently aiming to isolate and characterize proteins 3. Sommer, T., Bjerregaard-Andersen, K., that bind to the full length tankyrase enzyme, Simensen, S.M., Jensen, J.K., Jochimsen, B., Riss, a protein of more than 1200 residues and P.J., Etzerodt, M. and Morth, J.P. (2015) Enzymatic with several potential and verified interaction detection and quantification assay of isatin, a partners. We are therefore combining our putative stress biomarker in blood. ACS Chem. structural and biochemical studies with cellular Neurosci. 6, 1353-1360 assays, using the strong imaging platforms built up by Oddmund Bakke (UiO). External Funding In addition to NCMM funding, the group is Achievements in 2015 supported by the Research Council of Norway, The magnesium transporter A: a bacterial P-type the Norwegian Cancer Society, the Lundbeck ATPase dependent on cardiolipin and selectively Foundation, the Carlsberg Foundation and the sensitive to free magnesium in vitro. Blix Foundation. This study demonstrates, for the first time, that MgtA is highly dependent on anionic Group members phospholipids and in particular, cardiolipin. Postdoctoral fellows: The in vitro kinetic experiments performed Kaare Bjerregaard-Andersen (until August 2015) on detergent solubilized MgtA suggest that Kim L. Hein (until August 2015) cardiolipin acts as a magnesium chaperone. We Harmonie Perdreau Dahl further showed that MgtA is highly sensitive to Johannes Bauer 2+ 2+ free Mg (Mg free) levels in the solution. MgtA 2+ is activated when the Mg free concentration is PhD fellows: reduced below 10 µM and is strongly inhibited Saranya Subramani “The group is linking acid-base 2+ above 1 mM, indicating that Mg free acts as product Theis Sommer inhibitor. Furthermore, co-localization studies homeostasis with metal ion transport confirmed that MgtA is found in the cardiolipin Master Students: lipid rafts in the membrane. Combined, our Carolina Alvadia across the membrane” findings indicate that MgtA may act as a sensor Stefanie Ruhland (from April 2016) as well as a transporter of Mg2+ (1) . Principal engineer: 1. Subramani, S., Perdreau-Dahl, H. and Morth, Steffi Munack (until December 2015) J.P. (2016) The magnesium transporter A is Bojana Damnjanovic (from February 2016) activated by cardiolipin and is highly sensitive to free magnesium in vitro. Elife. 5, 10.7554/ Collaborations eLife.11407 Oddmund Bakke (UiO), Bernd Tiede (UiO), Jan K. Jensen (Aarhus University), Michael Etzerodt Targeting stress: development of a novel assay based (Aarhus University) , Ian Mills (NCAMM and on structural analysis of the manganese dependent Queens University Belfast) enzyme isatin hydrolase.
The product state, mimicked by bound thioisatinate, reveals a water molecule that bridges the thioisatinate to a proton wire in an adjacent water channel and thus allows the proton released by the reaction to escape only when the product is formed. The functional proton wire present in IH-b represents a unique
24 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 25 RESEARCH GROUPS
Antoni Hurtado
Breast Cancer Group
The main interest of my research is to understand that FOXA1 mediates proliferation driven by the mechanism of hormone resistance in breast selective cell-signaling pathways. This additional cancer. Breast cancer is a heterogeneous disease role independent of ER function would at least and gene expression profiling has classified in part explain resistance to hormone therapy. the tumors into several intrinsic subtypes To test this idea, we have initiated a study with with distinct prognostic significance. Luminal different inhibitors targeting the RTKs Fibroblast subtypes are the most frequent (around 70%) Growth Factor Receptor (FGFR) or Janus kinase and they express Estrogen Receptor alpha (ER). (JAK) in tamoxifen resistant breast cancer cell Estrogen-ER interaction induces a transcriptional lines. JAK is a non-receptor tyrosine kinase that program, which culminates in proliferation. transduces cytokine-mediated signals via the Estrogen signaling exerts its growth-promoting JAK-STAT pathway. Our results show that the effects by inducing ER binding to many chromatin inhibition of FGFR or JAK also prevents FOXA1 sites, which leads to the altered expression of chromatin interaction. Altogether, these results coding and non-coding RNAs. Treatment with denote that multiple cell-signaling pathways anti-ER therapies inhibits its function, reduces might be required to control the functions of tumor growth and improves survival. The anti- FOXA1 in hormone-resistant contexts. estrogen treatments are effective in clinical We now aim to elucidate which cell-signaling practice. However, a major clinical limitation is pathways control FOXA1 and to test drugs the development of resistance to these therapies targeting those pathways as potential inhibitors and this is the main focus of our research. of tumor growth in hormone-resistant breast cancers. In collaboration with Dr. Anne Jorunn Description of the Group’s Research Stokka (responsible for the Chemical Biology Elucidating the role of cell-signaling pathways Platform at the Biotechnology Center of Oslo) we controlling FOXA1 functions in Breast Cancer will apply high-throughput screening to explore Previously, we published that FOXA1 expression the ability of kinases or phosphates inhibitors to was key in the response to Tamoxifen-ER control FOXA1 binding in a systematic manner. (Hurtado, Nat Genetics 2011). Hence, a high Moreover, we aim to test how drugs inhibiting expression of FOXA1 in primary tumors could FOXA1 chromatin interaction influence tumor predict a good prognosis of ER-positive breast growth. In collaboration with Dr. Sørlie and Dr. cancer after adjuvant endocrine therapy. Mælandsmo at the Institute for Cancer Research However, the expression of ER and FOXA1 (Radiumhospitalet, Oslo University Hospital) we is retained in the metastatic sites. We have will use an ER positive breast tumor model that demonstrated that HER2/HER3 controls the has been successfully established by implantation FOXA1-regulated transcriptional program of biopsy tissue from primary breast carcinomas responsible to trigger proliferation and in SCID mice. We have recently demonstrated metastases in breast cancer independently of ER that this model is positive for the expression (Katika et al, in submission). These results suggest of FOXA1 (Katika et al.). To validate whether
26 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 27 RESEARCH GROUPS ANTONI HURTADO “The main goal of the group is to understand the mechanism of hormone resistance in breast cancer”
those inhibitors might be used as a therapeutic Searching for novel mechanisms of action for the anti- actions provides an excellent opportunity to Collaborations alternative for patients with poor response to ER drugs Fulvestrant and Tamoxifen understand the mechanism of action of these Dr. Therese Sørlie and Professor Anne-Lise anti-ER therapies, the most promising drugs will The initial understanding of the mechanism drugs and therefore has important clinical Børresen-Dale (Oslo University Hospital, Oslo, be also tested in animals treated with the anti-ER of action of anti-ER is based on the idea that implications. Norway) – Crosstalk between FOXA1 and HER2 cancer drug Fulvestrant. those compounds interact exclusively with ER. breast tumors. However, the more we understand about the Achievements in 2015 Understanding how Tamoxifen represses estrogen- molecular mechanisms of even targeted drugs, • Paper submitted to Nucleic Acids Research Dr. Anne Jorunn Stokka (The Biotechnology mediated transcription the more we realize that they are generally (NAR): the work performed by Elisa Fiorito Center, Oslo, Norway) – Identification and Tamoxifen action is thought to occur through promiscuous with regard to their biological and Yogita Sharma has been very well re- characterization of tumor-specific cell signaling its competition with estrogen to interact with targets and effects. The simplified view of ‘one ceived by the journal Nucleic Acid Research. pathways regulating FOXA1. ER, which inhibits the ability of the receptor to drug, one target’ clearly does not hold true. Hitting Currently, the work is ready for re-submis- initiate transcription. However, it has been also multiple targets can enable a drug to be applied sion. Prof. Vessela Kristensen (Oslo University Hospital, described that tamoxifen shows agonistic activity therapeutically in several potentially unrelated • Best poster prize at the Summer Spetzes Oslo, Norway) – Breast Cancer susceptibility loci (Frasor, Cancer Res 2006) or an incomplete diseases; or, if more than one of the drug’s targets School for Nuclear Receptors: Elisa Fiorito and gene expression. inhibition of a subset of estrogen-regulated genes are involved in pathways relevant to a particular was awarded at this FEBS workshop with (Hurtado, Nat Genetics 2001) in breast cancer disease, the drug may have increased efficacy her CTCF work. Dr. Camilla Kaulsrad (Haukeland University cell lines. Yet, the precise mechanism by which for this therapeutic application. For instance, • Selected abstract for EMBO Nuclear Receptor Hospital, Bergen) – Role of FoxA1 in endometrial tamoxifen executes transcriptional repression the anti-ER drugs Tamoxifen and Fulvestrant meeting: CTCF work submitted to the journal cancers and response to anti-ER therapies. or partial induction is still unknown. Previously, also target other proteins than ER. It seems that Nucleic Acids Research was selected for a we reported that Tamoxifen requires PAX2 to those drugs increase Bcl-2 levels and inhibit the talk at this meeting. Dr. Meritxell Bellet (Vall-Hebron Research repress the transcription of the oncogene ErbB2 growth of breast carcinoma cells by modulating • Scientia Fellowship award: Sachin Sign has Institute, Barcelona, Spain) – Analysis of clinical (Hurtado, Nature 2008). Data of our group PI3K/AKT, ERK and IGF-1R pathways (Long, S et been awarded this fellowship. benefit for therapeutic adjuvant treatment with point at SNAIL and PAX2 as critical cooperating al. JBC, 2006). These results are supported by • The group was awarded with two new progesterone and vitamin D in breast cancer regulators of transcriptional repression the fact that a significant number of ER negative grants: Frimedbio Young Talent Grant from patients. coordinated by Tamoxifen. Interestingly, the patients are responsive to Tamoxifen (Li-Heng the Research Council of Norway as well as an interaction of these cooperating transcription Yang, J of Breast Cancer, 2012). Hence, one might Open Project grant from Helse SørØst. Dr. Pere Gascon (IDIPAPS, Hospital Clinic, factors does not seem to be random. Instead, we think that hormone-resistance might also occur Barcelona, Spain) – Investigating the role of have identified that promoter regions of a subset via mechanisms independent of ER. External Funding microenviroment in therapy resistant patients. of estrogen-regulated genes (~18%) are enriched The Norwegian Cancer Society (Principal with SNAIL in breast cancer cells treated with We propose a multitiered systems-level approach Investigator) tamoxifen. We believe that the presence of to understand the effect of anti-ER drugs on Helse Sør-Øst (Principal Investigator together those cooperating factors might be necessary breast cancer inhibition. We aim to define with Dr. Therese Sørlie) for tamoxifen repressive action, whereas the direct targets of Fulvestrant or Tamoxifen by UiO grant (Principal Investigator) absence of those factors might explain the applying breast cancer cell line protein extracts Research Council of Norway, Frimedbio Young agonistic activity of tamoxifen. All together, to Tamoxifen or Fulvestrant affinity matrices and Talent Grant (Principal Investigator) we propose that these cooperating factors identified binding interactions using LC-MS/MS. might be functioning as general ER-associated This approach has the advantages of examining Group members transcriptional regulators for anti-ER drugs and the entire proteome expressed in the disease- Siv Gilfillan - Head of Engineer more importantly, their interaction with ER relevant profile (Rix, U. Nat. Chem. Biol. 2009). Venkata Sateesh - Postdoc. might dictate tamoxifen outcome. Because fewer We believe that with this approach we will be Sachin Singh - Postdoc. than 10% of hormone receptor-positive breast able to surmount the complex action of anti- Elisa Fiorito - PhD student cancers are HER2 positive, the mechanism(s) ER drugs in a hormone-resistant breast cancer Shixiong Wang - PhD student underlying endocrine resistance remain to be context. Moreover, we believe this translational Torbjørn Amundsen Lien - Master student elucidated for the majority of ER-positive breast strategy could define a set of Tamoxifen and Signe Helene Kaarstad - Assistant cancers. We believe that the deregulation of the Fulvestrant interacting proteins, which could ER cooperative factors PAX2 and SNAIL might be considered as novel targets in breast cancer Three new postdocs will join the group within explain the hormone-resistance in ER+/HER2- treatment. Identifying protein mediators of 2016 breast tumors. Tamoxifen and Fulvestrant anti-proliferative
28 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 29 RESEARCH GROUPS
Judith Staerk Stem Cell Group
Our research focuses on deciphering molecular ry patient samples as well as patient-derived processes during normal and malignant induced pluripotent stem cells to analyse the hematopoiesis. Understanding the mechanisms potential of these iPS cells to differentiate into governing blood development is important, both hematopoietic progenitors, and to screen tran- to identify the underlying molecular events scription factor and miRNA libraries to identify that drive lifelong formation of blood cells, as candidate genes to reverse the potential block in well as to find pathways that are dysregulated in vitro blood cell differentiation. in blood disorders. The broad aims of my group are to i) identify epigenetic and genetic events Chronic lymphocytic leukemia (CLL) is a involved in hematopoietic specification and common hematological cancer in adults and early development, ii) decipher how the nuclear is characterized by clonal B cell expansion. In lamina influences hematopoietic development the past year, we assessed cell cycle defects and iii) identify underlying molecular causes of in CLL, and found that a significant number of myeloid blood disorders. To achieve these goals CD19+ B cells isolated from peripheral blood CLL we are using human pluripotent stem cells as samples are arrested in cytokinesis. We linked well as in vitro differentiation assays and animal the observed cytokinesis arrest to reduced models, along with primary samples isolated NuMA and TP53 protein levels, and showed that from patients suffering from hematopoietic several proteins known to be crucial for cell disorders, and combine these assays with genetic division, checkpoint and centromere function and genomic approaches. were significantly downregulated (manuscript in submission). Description of the Group’s Research Epigenetic dynamics during blood cell differentiation Lamin proteins and hematopoiesis Methylation of DNA is a key epigenetic mechanism A main focus of our group is to understand how to regulate gene expression. Recent discovery of the nuclear lamina influences hematopoietic TET proteins, which oxidize methylcytosine to development. Lamins are the most abundant 5-hydroxymethylcytosine (5hmC), uncovered proteins in the nucleus and form a filamentous a new epigenetic mark. We are interested in meshwork on the nucleoplasmic side of the defining the role of DNA methylation and 5hmC nuclear envelope. B-type lamins (LMNB) are during human hematopoiesis by assessing how ubiquitously expressed and have been shown deletion of Tet enzymes in human embryonic to be essential for cell survival, while A-type stem cells affects early mesoderm and lamins (LMNA) are expressed in differentiated hematopoietic commitment. cells and seem to be largely absent from early embryonic tissues. Dysfunction of the nuclear Projects with translational impact envelope is associated with altered nuclear Myelodysplastic syndromes (MDS) are a hetero- activity, impaired structural dynamics, and geneous group of clonal hematopoietic disorders altered gene expression. Surprisingly little is characterized by impaired hematopoiesis and a known about lamin function and regulation predisposition to developing acute myeloid leu- during hematopoiesis. We generated ChIP- kemia (AML). The underlying cause for MDS is Seq data sets to determine whether chromatin incompletely understood. We are using prima- binding by LMNA and LMNB1 is blood lineage
30 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 31 RESEARCH GROUPS JUDITH STAERK and differentiation specific (manuscript in External Funding preparation). Additionally, we are investigating 05/2013 - 05/2017: The Norwegian Cancer whether lamins and the nuclear architecture Society, PhD fellowship are affected in myelodysplastic syndrome and 04/2014 - 09/2017: Norwegian Research chronic myelo monocytic leukemia. Related Council, Stem Cell Call to these studies we are generating conditional 09/2014 - 08/2017: The University of Oslo, knockout and transgenic animal models to Postdoctoral fellowship determine the exact role of lamin proteins during 07/2015 - 06/2018: Research Council of hematopoietic development. Norway, Frimedbio Young Talent Grant Selected Key Publications from PI: 09/2015 – 08/2017 EU FP7-PEOPLE-2013- Staerk J and Constantinescu S.N. The JAK-STAT COFUND, Scientia fellow pathway and hematopoietic stem cells from the Group members JAK2V617F perspective. JAK-STAT. 2012 Volume 1:3, Head Engineer: 2012 Kirsti Præsteng
Staerk J, Dawlaty MM, Gao Q, Maetzel D, Hanna Postdoctoral fellows: J, Sommer CA, Mostolovsky G, Jaenisch R (2010) Safak Caglayan Reprogramming of human peripheral blood cells Artur Cieslar-Pobuda (from February 2016) to induced pluripotent stem cells. Cell Stem Cell. Adnan Hashim 7(1):20-4. Ida Jonson Marie Rogne Staerk J, Defour JP, Pecquet C, Leroy E, Poirel HA, Brett I, Itaya M, Smith SO, Vainchenker W, PhD fellows: Constantinescu SN (2011) Orientation-Specific Julia Madsen-Østerbye Signaling by Thrombopoietin Receptor Dimers. Oksana Svärd EMBO J. 30(21):4398-413. “The group aims to understand molecular Collaborations Staerk J, Lyssiotis CA, Medeiros LA, Bollong M, International scientific collaborations processes during normal and malignant Foreman RK, Zhu S, Garcia M, Gao Q, Bouchez • Stefan N Constantinescu (Ludwig Institute LC, Lairson LL, Charette BD, Supekova L, Janes J, for Cancer Research, Brussels, Belgium). hematopoiesis” Brinker A, Cho CY, Jaenisch R, Schultz PG (2011) Collaboration on cytokine receptor signaling Pan-Src Family Kinase Inhibitors Replace Sox2 during in normal and malignant hematopoiesis. the Direct Reprogramming of Somatic Cells. Angew • Petr Bartunek (Institute of Genetics, Prague, Chem Int Ed Engl. 50(25):5734-6. Czech Republic). Collaboration on cell type specification and zebrafish in vivo models Lyssiotis CA*, Foreman RK*, Staerk J*, Garcia M, • Christian Schmees (NMI Reutlingen, University Mathur D, Markoulaki S, Hanna J, Lairson LL, of Tübingen, Germany). Collaboration on Charette BD, Bouchez LC, Bollong M, Kunick C, generating microRNA libraries from healthy Brinker A, Cho CY, Schultz PG, Jaenisch R (2009) and myelodysplastic syndrome patients Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation National scientific collaborations of Klf4. Proc Natl Acad Sci USA. 106(22):8912-7 • Geir Tjønnford and Ingunn Dybedal, OUS (*equal contribution) Rikshospitalet, Department of Hematology • Kjetil Tasken, NCMM, UiO. Staerk J, Lacout C, Sato T, Smith SO, Vainchenker • Karl-Johan Malmberg, Dept. of Immunology, W, Constantinescu SN (2006) An amphipathic Institute for Cancer Research, UiO. motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor. Blood 107(5):1864-71.
James C, Ugo V, Le Couedic J-P, Staerk J, Delhommeau F, Lacout C, Berger R, Garcon L, Raslova H, Bennaceur A, Villeval J-L, Constantinescu S.N, Casadevall N, Vainchenker W (2005) A unique clonal JAK2 mutation leading to constitutive signaling causes polycythemia vera. Nature 434(7037):1144-8.
32 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 33 Research Collaboration with Oslo University Hospital
The overall objective of NCMM is to conduct cutting-edge research in molecular medicine and facilitate translation of discoveries in basic medical research into clinical practice. In order to enable translational research, NCMM has developed strong links to South-Eastern Norway Regional Health Authority and its subsidiary Oslo University Hospital (OUH).
Cancer Center, organizationally under the with a special interest in heart electrophysiology All NCMM Group Leaders have adjunct positions The Department of Infectious Diseases runs Division of Cancer Medicine, Surgery and and membrane pumps. The institute is involved in in clinical or para-clinical departments at OUH. an extensive research programme, especially Transplantation at OUH. extensive collaborations with other laboratories Our experience so far with these affiliations is related to the diseases HIV/AIDS and hepatitis. in clinical departments at the OUH and is that they facilitate clinical collaborations, give The department is also responsible for a variety Department of Cancer Genetics, Institute interacting with colleagues both nationally and group leaders better access to patient materials, of advanced educational courses in infectious for Cancer Research (OUH) internationally. The institute is organized under biobanks and clinical trials and that they are diseases and is organized under the Medicine The main goal of the department is to follow the the Division of Cardiovascular and Pulmonary crucial to facilitate translational research. These Division at OUH. linear time course of predisposition, initiation, Disease at OUH. research collaborations have already resulted in early stages and advanced disease and to a number of joint publications and NCMM Group Department of Molecular Oncology, dissect the molecular mechanisms triggered Department of Haematology, (OUH) Leaders also report on several joint applications Institute for Cancer Research (OUH) at each stage. Furthermore, the department is Patients with all types of blood diseases are for funding of new collaborative projects. The Institute for Cancer Research has focusing on how to follow the multi-dimensional treated at the Department of Haematolgy. NCMM Group Leaders currently hold adjunct strong international research groups within interactions at various levels in a systems biology The department’s goal is to deliver excellent appointments at the following departments: biochemistry, cell and tumor biology, genetics, approach to better perform risk estimation, patient care, provide advanced teaching in the radiation biology, immunology and cancer prognostication and prediction. field of blood diseases and perform research Department of Infectious Diseases prevention. For more than 30 years there has of high international standard. Furthermore, (OUH) been a close interaction between researchers at Institute for Experimental Medical the department conducts research in most of The department is the largest of its kind in this institute and cancer surgeons, oncologists Research (OUH) the areas in which treatment is provided. The Norway and covers the entire field of infectious and pathologists. The emphasis on translational The Institute for Experimental Medical Research department is organized under the Division of medical conditions, such as tropical medicine, science has resulted in numerous clinical is primarily focusing on heart disease research Cancer Medicine, Surgery and Transplantation HIV, tuberculosis as well as severe and life protocols based on in-house research and the as well as teaching. In particular, the institute is at OUH. threatening bacterial and viral infections. institute is a key partner in the Comprehensive performing research on congestive heart failure
34 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 35 From Disease Mechanisms to Clinical Practice
NCMM group leaders have so far listed some 25 and interventional clinical studies in the fields of therapy and disease mechanisms as well as in the molecular markers, diagnostic and monitoring areas.
On-going development in the area of therapy On-going development in the area of • Immunomodulating cAMP antagonists and PKA diagnostics and monitoring anchoring disruptors (immunodeficiency and • Prostate cancer markers – serum/plasma protein anti-tumor immune responses) biomarkers, overlapping genetic risk factors for • Disruption of the PKA-AKAP18d-phospholam- prostate cancer and blood lipid traits, tran- ban-Serca2 complex for cardio-protective effect script-based biomarkers in urine and circulating in ischemia-reperfusion damage tumor cells. Evaluation of protein biomarkers • Small molecule inhibitors of OGlcNAc tran- in blood samples from patients with prostate ferase and de novo purine biosynthesis enzymes cancer undergoing radiotherapy with or without to destabilize oncogenic signaling in prostate androgen deprivation therapy. cancer • New biochemical markers for MAO diseases & • Bromodomain inhibition to enhance respons- early screen Parkinson es to androgen deprivation/anti-androgens in • Single cell analysis of inflammatory signaling prostate cancer events by fluorescent cell bar-coded phos- • Targeting of Na+/K+-ATPase and Serca2 in neuro- pho-flow cytometry for diagnostics and moni- “The extent of clinical collaborations and biology and heart disease toring • Suppression mechanisms by regulatory T cells • Regulatory T cell markers in HIV and other im- with application in immune diseases, autoim- mune diseases activity with translational and clinical munity and cancer • Flow cytometry-based biomarkers in mitogenic • iPSC disease-modeling of blood disorders signaling pathways for drug sensitivity screens studies continues steadily at a high level” • Assay development and structural analysis of the membrane proteins in virulence operon Proof-of-concept in humans mgtCBR specific to pathogenic bacteria • Effect of anti-inflammatory drug (COX-2 inhib- • Structural analysis of the membrane proteins itor Phase IIA) on immune function (CD38 o.a.) linked to the virulence operon mgtCBR specific and vaccine responses in HIV-infected patients to pathogenic bacteria • Vaccine and radiation in prostate cancer – Ulti- • Structural analysis of bicarbonate transporters movacs Trial and investigation of pH homeostasis • Secondary preventive effect of acetyl salicylic • Enzymatic detection and quantification assay of acid in metastatic colorectal cancer (to start) isatin, a putative stress biomarker in blood. • Investigation of the Membrane-associated RING finger protein (MARCH) E3-ligases Furthermore, NCMM is involved in two translational • Cancer drug sensitivity screening on patient KG Jebsen Research Centres that were established samples with set of approx. 400 cancer drugs to in 2013. The KG Jebsen Foundation has stated that assist clinical decision on individualized therapy translational research is of high priority to them choices in chronic lymphatic leukemia, multiple and the Norwegian Ministry of Health and Care myeloma and ovarian cancer Services has also highlighted this type of research • Elucidation of the mechanism of action of as an important priority area for strengthening medroxiprogesterone injection before sur- clinical research. NCMM is connected to the KG gery as a treatment that improves overall and Jebsen Centres Inflammation Research (led by Prof. disease-free survival of ER+/HER2- breast cancer Guttorm Haraldsen) and Cancer Immunotherapy patients (led by Prof. Johanna Olweus). • Development of CAMKK2 inhibitors for the treat- ment of prostate cancer.
36 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 37 (TREC), Department of Clini- (newly appointed) NCMM Associate cal Medicine, UiT, The Arctic • Professor Anders Sundan, University of Norway and Department of Cancer Research Investigators University Hospital of North and Molecular Medicine, Nor- Norway (newly appointed) wegian University for Science LARS AKSLEN • Professor Arne Klungland, and Technology (NTNU) (newly Director, Professor of pa- NCMM Associate Department of Microbiology, appointed) thology, Senior Consultant Division of Diagnostics and Intervention, Institute of Clin- NCMM Young Associate Tumor Biology Research ical Medicine, Oslo University Investigators: Group Investigators and Young Hospital and Institute for Basic • Dr. Sören Abel, Department Lars A. Akslen (MD, Medical Sciences, University of of Pharmacy, University of PhD) is a specialist Oslo (re-appointed) Tromsø and Harvard Medical in surgical pathol- Associate Investigators • Professor Per E. Lønning, School (appointed 2014) ogy. He is directing Section of Medicine, University • Dr. Thomas Arnesen, Depart- the Tumor Biology of Bergen and Department of ment of Molecular Biology, Uni- Research Group Oncology, Haukeland Universi- versity of Bergen and Depart- (since the establishment in ty Hospital (re-appointed) ment of Surgery, Haukeland 1995) at Department of Clin- • Professor Karl-Johan Malm- University Hospital (newly ical Medicine (University of berg, Department of Cancer appointed) Bergen). Since 2013, Akslen Immunology, Institute for • Dr. Lorena Arranz, Depart- is also the director of Centre Cancer Research, Oslo Univer- ment of Medical Biology, Uni- for Cancer Biomarkers (CCBIO), sity Hospital and Institute for versity of Tromsø and Depart- a Norwegian Centre of Excel- NCMM aims to continue to ed group leaders and where Associate Investigators and Clinical Medicine, University of ment of Hematology, University lence (www.ccbio.no). Akslen´s develop its scientific and the conditions are similar to Young Associate Investigators Oslo (newly appointed) Hospital of Northern Norway team, and now CCBIO, are technological capabilities by those offered to NCMM Group were evaluated by a Selection • Professor Erlend Nagelhus, (UNN) (appointed 2014) engaged in translational cancer establishing strong collabora- Leaders, can offer an affiliation Committee taking into account Department of Molecular Med- • Associate Professor Simona research with a strong focus tive links with key scientists to NCMM during the call. In scientific excellence, trans- icine, Institute of Basic Medical Chera, Department of Clinical on the exploration and valida- and research groups across the latter case NCMM must lational merit, compatibility Sciences, University of Oslo and Science, University of Bergen tion of novel biomarkers for Norway, thus facilitating be contacted beforehand and with the NCMM mission and Department of Neurology, Oslo (newly appointed) biologically based classifica- translational networking. The will assist in the recruitment added value for NCMM. The University Hospital (appointed • Professor Trude H. Flo, Centre tion and grading of malignant Associate Investigator cate- process of the NCMM Young Committee found that the call 2014) of Molecular Inflammation tumors as a better guide for gory is meant for outstanding Associate Investigators. Both was highly competitive with • Professor Pål R. Njølstad, KG Research (CEMIR) and Dept. of more precise and cost-effective scientists who are currently Associate Investigators and excellent applications and in Jebsen Centre for Diabetes Cancer Research and Molecular cancer treatment. based in Norway, whose ex- Young Associate Investigators October 2015 the NCMM Board Research, University of Bergen Medicine, Norwegian Universi- pertise is compatible with the continue to work at their host appointed five new Associate and Department of Pediatrics, ty for Science and Technology At present, the team is focus- NCMM research areas and institutions but are credited Investigators and seven new Haukeland University Hospital (NTNU) (newly appointed) ing its efforts in two areas: 1. who are interested in collabo- an affiliation to NCMM and the Young Associate Investigators. (re-appointed) • Dr. Espen Melum, Norwegian studies of the tumor microen- rating with NCMM. Associate Nordic EMBL Partnership. Altogether, the NCMM Asso- • Professor Johanna Olweus, KG PSC Research Center, Depart- vironment, especially tu- Investigators are expected to ciate Investigator and Young Jebsen Center for Cancer Im- ment of Transplantation Med- mor-vascular interactions and contribute with their expertise NCMM has had twelve As- Associate Investigator network munotherapy, Department of icine, Oslo University Hospital markers of angiogenesis; 2. in molecular and translation- sociate Investigators in the now consists of 22 excellent Cancer Immunology, Institute (newly appointed) molecular markers of aggres- al medicine and be active in first 5-year period. Based on investigators: for Cancer Research, Oslo Uni- • Associate Professor Siver sive tumor behavior, related mentoring activities towards applications, seven Associate versity Hospital and University Mostue, Department of Cir- to proliferation and cell cycle newly recruited NCMM Group Investigators were re-appoint- NCMM Associate of Oslo (newly appointed) culation and Medical Imaging regulation. Gene expression Leaders and Young Associate ed in 2015. In addition, one Investigators: • Professor Ole P. Rekvig, De- and Department of Laboratory studies are combined with Investigators. NCMM group leader was ap- • Professor Lars Akslen, Centre partment of Medical Biology, Medicine, Norwegian Universi- proteomic profiling and single pointed Associate Investigator for Cancer Biomarkers (CCBIO), University of Tromsø and ty for Science and Technology marker validation in patient NCMM has also initiated a in 2014 when he rotated out of University of Bergen and University Hospital of Northern (NTNU) (newly appointed) cohorts. Experimental valida- Young Associate Investigator the Centre. Furthermore, two Haukeland University Hospital Norway (re-appointed) • Dr. Hege Russnes, Department tion by animal and cell models program for young talented re- investigators at the Universi- (re-appointed) • Professor Helga B. Salvesen, of Pathology and Department is done in selected studies. searchers that are recruited as ty of Tromsø were appointed • Professor Ole A. Andreassen, Department of Clinical Medi- of Cancer Genetics, Institute of An overall goal is to extend group leaders at another insti- NCMM Young Associate In- Division of Mental Health and cine, University of Bergen and Cancer Research, Oslo Univer- studies of prognostic and tution. Young Associate Inves- vestigators in 2014 in a joint Addiction, Oslo University Hos- Department of Obstetrics and sity Hospital (newly appointed) predictive biomarkers towards tigators are identified by one recruitment process between pital and Institute of Clinical Gynaecology, Haukeland Uni- • Dr. Pia Abel zur Wiesch, an integrated role in clinical of two routes: either by direct UiT/ University Hospital of Medicine, University of Oslo versity Hospital (re-appointed) Department of Pharmacy, trials and personalized patient application to NCMM in open North Norway and NCMM. (re-appointed) • Professor Anne Simonsen, University of Tromsø and Yale management. As examples, the calls or where universities and Following an open call an- • Professor John-Bjarne Hansen, Department of Molecular Med- School of Public Health, US team is now working on trials other research institutions that nounced in the spring 2015, KG Jebsen – Thrombosis Re- icine, Institute of Basic Medical (newly appointed) of anti-angiogenesis treatment wish to recruit young, talent- applications for the status as search and Expertise Centre Sciences, University of Oslo (breast and renal carcino-
38 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 39 NCMM ASSOCIATE INVESTIGATORS AND YOUNG ASSOCIATE INVESTIGATORS ma, malignant melanoma) to about disease mechanisms. for finding common denomi- also include genes affecting KARL-JOHAN ERLEND A. explore the potential clinical Medications are an important nators for the development of post-translational modifica- MALMBERG NAGELHUS value of several candidate part of treatment of diseases, psychosis. tions in RNA and proteins; Professor Professor biomarkers. and targets for the group are epigenetic inheritance. to gain more knowledge about Natural Killer Cell Biology GliaLab The vision of CCBIO is to dis- how drugs work and how reac- ARNE KLUNGLAND and Cell Therapy Erlend A. Nagelhus obtained cover, validate and translate tions occur. Professor and Head of PER E. LØNNING Karl-Johan Malmberg is a his MD (1993) and functional cancer biomarkers Section Professor physician-scien- Dr. Med. (1998) at to improve biological under- Research Focus: Discover new tist who performs the University of standing, diagnosis and treat- disease genes by severe mental Laboratory for Genome The Breast Cancer Group basic, translational Oslo (UiO). After ment of aggressive cancer. The disorders through participation repair and regulation The Breast Cancer and clinical re- clinical training he research activity is organized in international consortium, Arne Klungland did Group is located in search in the fields returned to UiO in three areas: basic studies with special interest for poly- his PhD and post- the Mohn Cancer of Hematology/On- as a postdoc (2004-2005) and and animal models, discovery genic effects. Exploring disease doctoral training Research Labora- cology and Immunology/Innate senior scientist (2005-2008; and validation of new biomark- genes and examine the context with Erling Seeberg tory at Haukeland immunity. The long-term goal Centre for Molecular Biology ers in human samples, and of clinical, cognitive and brain (Oslo) and Nobel University Hospital, of his laboratory is to advance and Neuroscience, a Norwe- clinical studies, in addition to organic changes in well-de- prize laureate 2015 Bergen and is headed by Pro- our fundamental understand- gian Centre of Excellence). projects on ethics and econo- scribed clinical material. This Tomas Lindahl (London), two fessor Per Eystein Lønning. The ing of natural killer (NK) cell Nagelhus has also been a my within personalized cancer operation uses biostatistical pioneers in the discovery of research program of the group development and function, Research Scholar at Center for management. The CCBIO methods and analysis. An im- fundamental processes for the is translational and assesses and use this progress to design Translational Neuromedicine, Research School on Cancer portant part of the activity is to repair of DNA damage. During different aspects of cancer new immunotherapeutic Department of Neurosur- Studies has been established to study the mechanism by drugs. these years, they focused on related to hormonal therapy approaches and clinical trials gery, University of Rochester improve education and career The focus is currently on the the mechanistic insight in the and chemotherapy as well as for patients with cancer. The Medical Center, Rochester, NY development. immune system; which genes repair of alkylated, deaminated cancer risk factors. Malmberg laboratory focuses (2007-2008) and Group Leader affect this, how it is related and oxydized bases in DNA on basic questions concerning at NCMM (2009-2014). Nagel- to psychological symptoms and on developing biological Important issues addressed 1) the formation of killer cell hus was appointed Professor OLE A. ANDREASSEN over time, and what role drugs systems to assess their endog- by the group include somatic immunoglobulin-like receptor of Physiology at UiO in 2013. Professor, Director play in this context. We also enous levels and character. mutations causing cancer cells (KIR) repertoires and regula- In addition, Nagelhus is an want to study the differenc- Throughout his independent to be resistant to treatment, tion of effector cell function, 2) Adjunct Professor at the Uni- Translational psychiatry es and similarities between career he has continued to germline factors influencing translational questions of how versity of Rochester, and holds The group focuses disease groups, thus generat- focus on the role of novel mod- the risk of cancer affecting NK cells may be function-en- an adjunct position as research on the relationship ing knowledge about what are ifications in DNA and RNA and clinical progression of can- abled for anti-cancer activity scientist at Department of between genetic disease-specific processes and to identify genes required for cers and side effects during and 3) clinical studies in the Neurology, Oslo University risk, environmental what are phenotype-related their dynamic regulation. Yet, treatment, hormones and context of allogeneic stem cell Hospital. He is also Head of the factors and biolog- processes. the focus has been adapted to their role in cancer develop- transplantation (HSCT) and Letten Centre. ical variables, and regulatory modifications and to ment and treatment of various adoptive cell therapy. how these are related to clin- Projects: Polygenic architecture: unravel the biological function hormone-sensitive cancers as The GliaLab explores roles ical disease forms and brain We use major international of their readers and erasers well as tumor heterogeneity. In 2012 the group relocated of astrocytes – the predom- organic relationship in serious genetics studies along with (EMBO 2006, 2007, Mol Cell The work is mainly focused on from the Karolinska Institutet inant glial cell type in brain mental illness. new analysis tools to identify 2013, Nat Comm 2011, 2013, cancers arising in the breast, (Stockholm) to Oslo University - in health and disease by the polygenic contribution to Nature 2007, PLoS Gen 2010, but also includes cancers of Hospital. At the Institute for 2-photon laser scanning mi- Aims: Identify the causes and disease development in bipolar Genes & Dev 2015). In 2015 the the ovaries, prostate and the Cancer Research, Oslo Univer- croscopy. The group focuses identify disease mechanisms disorder, schizophrenia and re- Klungland group identified 1 gastrointestinal tract as well as sity Hospital, the Malmberg on glial mechanisms for brain in schizophrenia and bipolar lated disorders. Genotype-phe- more reversible modification in malignant melanomas. The aim group has established an inter- waste removal, ionic (dys)-ho- disorder using a translational notype mapping: We identify RNA (in review). is to reveal the mechanisms disciplinary and translational meostasis and neuron-glia-vas- approach. The main focus is the clinical and brain organic regulating the behavior of research program aiming at cular signaling. Disease models on genetic factors, since severe correlate genetic vulnerabil- Today, the group aims to individual cancers, as well as developing cellular thera- include mesial temporal lobe mental disorders have a high ity factors in well described elucidate new mechanisms of mechanisms of cancer develop- pies for cancer based on new epilepsy/hippocampal sclero- degree of heredity, but few ge- national and local cohorts of methylation and demethyla- ment and therapy resistance. insights into NK cell biology. sis, migraine and Alzheimer’s netic factors are known. There patients, and how this is relat- tion for regulation of the mam- A deeper understanding of Since 2015 Malmberg holds a disease. The group uses the is also little knowledge about ed to the proceeding. Immune malian genome and to address cancer cell biology will result visiting professorship at the chronic cranial window prepa- how genetic factors are related System: We have a series of genome instabilities associated in better identification of risk Karolinska Institute and leads ration in combination with to environmental risk factors. studies that explores genet- with cancer development and factors and more optimal treat- a Nordic program in NK-cell virally delivered genetically Furthermore, the connection ic variants, serum markers, possible other diseases. The ment of patients. based immunotherapy. encoded fluorescent sensors to to different disease charac- drugs and brain mechanisms group works closely together shine light on cellular and mo- teristics in patients, including related to different aspects of with the clinic at Oslo Univer- lecular events in the cerebral clinical, cognitive and brain or- the immune system. Psychosis sity Hospital. For most projects, cortex and hippocampus of ganic relationship is unknown. across disorders: We have sev- novel mutants are designed awake behaving mice. In charting such contexts, the eral studies on developmental and tested in cells and model goal is to gain more knowledge disorders and aging processes organisms. Current models
40 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 41 NCMM ASSOCIATE INVESTIGATORS AND YOUNG ASSOCIATE INVESTIGATORS
PÅL R. NJØLSTAD JOHANNA OLWEUS The group has provided evi- Haukeland University Hospi- of several national and interna- Professor and Consultant Professor, Head of dence that mammalian B helical tal, being the first Norwegian ANNE SIMONSEN tional committees. She is also Physician Department of Cancer dsDNA has an immunogenic ESGO (European Society for Professor leading the Nordic Autophagy Immunology, Institute for potential that depends on the Gynecologic Oncology) accred- Network (2011-2015) and was KG Jebsen Center for Cancer Research, Director context in which dsDNA is pre- ited training center for gyneco- Autophagy Lab the main organizer of the 2013 Diabetes Research K.G. Jebsen Center for sented to the immune system. logic oncology, and the Centre Professor Anne EMBO Autophagy conference. Pål Rasmus Njølstad, Cancer Immunotherapy The most important is complex of Excellence CCBIO, co-direct- Simonsen received MD PhD, is Professor formation with immunogenic ed by Prof. Helga B. Salvesen. her Dr. Scient de- at the Department Immunotherapy and Antigen non-self (viral) DNA/chroma- With breakthroughs published gree in 1996 at the ANDERS SUNDAN of Clinical Medicine, presentation tin-binding proteins. These data in top-ranked general (Nature, University of Oslo, Professor University of Bergen Johanna Olweus have generated new paradigms PNAS, NEJM) and specialized Norway. From 1997- and consultant received her M.D. on the origin and pathogenic cancer journals (JCO, CR, CCR) 2004 she was a postdoc at the KG Jebsen Centre for physician at the Department of and her Ph.D. from impact of auto-antibodies to the research group has contrib- Norwegian Radiumhospital, Myeloma Research Pediatrics, Haukeland University the University of dsDNA/chromatin in SLE. uted to the discovery of new Oslo and the Salk Institute of The research group Hospital. Njølstad is also head- Bergen, Norway. potential treatment targets and Biological Studies, CA, USA. consists of 15 people ing the KG Jebsen Center for She is a specialist in A central element in the patho- markers for individualizing She is currently a Professor at devoted to basic, Diabetes Research. He has had Immunology and Transfusion genesis of progressive lupus gynecologic cancer care. the Institute of Basic Medical translational and research stays at the University medicine and is since 2008 Pro- nephritis relates to an acquired Sciences, University of Oslo, clinical aspects of of Chicago (Prof. Graeme I. Bell), fessor at the University of Oslo defect of chromatin metab- Key clinical challenges: gyneco- where she heads a research the hematological Harvard Medical School (Prof. C. as well as Head of Department olism in nephritic kidneys. logic cancers show significant group of eleven people. The cancer multiple myeloma. Ronald Kahn) and Broad Insti- of Cancer Immunology at the In- The primary cause for this is overlap for histological sub- overall objective of their Multiple myeloma is due to tute of Harvard and MIT (Prof. stitute for Cancer Research, Oslo a nearby complete and selec- types and clinical phenotypes, research is to characterize malignant transformation of David Altshuler). University Hospital Radiumhos- tive shut-down of renal DNase also recently supported by the molecular machinery antibody-producing plasma pitalet. Since 2013 she is also I gene expression. Rekvig and comprehensive molecular involved in regulation and cells in bone marrow, and His KG Jebsen Center consists of Director of KG Jebsen Center for colleagues have discovered a tumor profiling. The challenge execution of autophagy at a monoclonal immunoglobulin some 50 members with compe- Cancer Immunotherapy. Olweus new, hitherto unknown func- is now to translate the knowl- biochemical and cellular level is used as a biomarker of the tence in epidemiology, clinical and her research group are tion of DNase I. In response to edge into clinically meaningful and to integrate this knowl- disease. Multiple myeloma is investigations and treatment focusing on the development of the pro-inflammatory cytokine and applicable tests to improve edge in disease-related model considered an incurable disease trials, molecular genetics, CRIS- new strategies for T-cell based IL-1β, DNase I translocates from and individualize patient care. systems. The current main with a median survival from PR, genome-wide association cancer immunotherapy and the cytoplasm into the nucle- Our research environment is focus areas of the research time of diagnosis of 5-7 years. studies, genome sequencing, in-depth mechanistic analyses of us in a non-apoptotic context. presently in a unique posi- group are; 1) characterization However the patients show bioinformatics, cell biology, stem the immune responses in clinical Upon translocation, DNase I tion to take some of this new of the membrane remode- great heterogeneity in response cell research and animal models. immunotherapy trials. lost its endonucleolytic func- knowledge to clinical imple- ling and trafficking events to chemotherapy as well as to tion, bound to the Fas Recep- mentation studies. required for autophagosome the course of the disease. The Njølstad´s research is focused tor promoter region, induced formation, 2) identification group has research activities on monogenic diabetes having OLE PETTER up-regulation of the Fas Recep- The group aims to contribute of the molecular machinery both on the basic and clinical described new diabetes syn- REKVIG tor and promoted the cells to to more precision in gyneco- involved in selection of cargo aspects of multiple myeloma. dromes, including MODY8. The Professor FasR mediated apoptosis. This logic cancer care. By exploring for degradation by autophagy The basic research is centered group has also revealed that extends the function of DNase primary and metastatic lesions, and 3) understanding the role on how myeloma cell survive neonatal diabetes can be treated RNA and Molecular I to be an inducer of apoptosis. in parallel with comprehensive of autophagy in fusion-pro- in bone marrow and the role of with sulfonylurea tablets instead pathology Research Group This may explain one reason for clinical annotation, advanced tein-associated leukemia and inflammation, oncogenic acti- of insulin. He has achieved Rekvig and his extensive apoptotic cell death imaging and drug testing in protein aggregate-associated vation and the clonal evolution competitive research funding, colleagues have in lupus nephritis. preclinical models, the group neurodegenerative disease. of the malignant cells, and how e.g. from the European Research developed pro- will define promising targets Our areas of methodological myeloma cells escape immune Council (ERC AdG), Novo Nor- jects focusing on and conduct molecularly based expertise are high-throughput surveillance. The clinical disk Foundation, the Research origin and impact HELGA B. clinical trials. Individualized cell-based assays, bioinformat- research is centered on why Council of Norway as well as the of autoantibodies SALVESEN treatment and follow-up based ics, various genome editing some patients respond well to University of Bergen and Helse against dsDNA and chromatin Professor, Co-Director on biomarker-determined risk approaches, state-of-the art chemotherapy whereas others Vest. structures. These studies aim to CCBIO profiles will be implemented imaging techniques, a range of do not, i.e. mechanisms of in- understand the pathogenesis of as a study in parallel whilst protein interaction assays, as herent and acquired resistance lupus nephritis, the most serious Bergen Gynecologic assessing quality of life and well as mammalian cell culture to common drugs, and on how manifestation of Systemic lupus Cancer Research Group costs. systems and in vivo model the clonal evolution of malig- erythematosus (SLE). These The Bergen gy- organisms (Zebrafish). nant cells can be monitored studies aim to understand toler- necologic cancer in the clinic. The studies are ance to dsDNA/chromatin struc- research group has The team benefits from an based on extensive use of pa- tures, how it is controlled and 23 active members extensive interactive network tient material and in particular terminated in disease as well as focusing on clini- of national and internation- bone marrow aspirates taken to describe the pathogenesis of cal and molecular al collaborations. Professor for diagnostic purposes, as well lupus nephritis with focus on aspects of gynecologic cancers. Simonsen is on the Autophagy as mice and in vitro cellular renal chromatin metabolism. The group is embedded in editorial board and a member models of myeloma.
42 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 43 NCMM ASSOCIATE INVESTIGATORS AND YOUNG ASSOCIATE INVESTIGATORS
NCMM Young and into the environment. In modification in human cells cells. Taking the hematopoietic and was appointed as member to define two distinct, naturally particular, the group is inter- catalyzed by N-terminal acet- system as a primary model, the of the Department of Hematol- occurring β-cell regeneration Associate ested in the c-di-GMP sec- yltransferases (NATs). Their group aims at understanding ogy at the University Hospital mechanisms based on cell-re- Investigators ond messenger network that goals range from defining the the molecular mechanisms of North Norway (UNN) in programming and controlled controls important adaptation NAT-machinery and the molec- of stem cell malignant trans- January 2015. by an age-dependent switch mechanisms during infection ular mechanisms of N-terminal formation and the complex (Thorel et al., 2010, Nature; SÖREN ABEL and its impact on population acetylation to establishing the interactions of this cell with Currently, the group consists Chera et al., 2014, Nature). Group Leader, Visiting dynamics, bacterial viru- links between NAT-defects or its surrounding microenvi- of two postdocs, two PhD Assistant Professor lence and persistence under NAT-overexpression and dis- ronment, with a focus on students and a head engineer. Chera is now exploring new changing conditions. They eases like cancer and recently inflammation and signaling Lorena Arranz is supported strategies aiming at enhancing Infection Biology employ deep-sequencing based discovered syndromes. onco-metabolites. The group’s by a joint meeting among UiT, the β-cell mass in diabetic con- Sören Abel re- methods to infer the spread of goal is identification of novel UNN and the Regional Authori- ditions. Her group also plans to ceived his MSc in pathogens within and between Their investigations have therapeutic targets of potential ties of Northern Norway (Helse characterize and compare the biochemistry and hosts and combine it with contributed to the under- clinical interest. Nord), Young Research Talent cellular processes as well as molecular biology bacterial genetics and live cell standing of the physiological grants from the Norwegian the gene-environment interac- from the University microscopy. Understanding and clinical importance of The group is led by Dr. Lore- Research Council (Stem Cell tions occurring in monogenic of Kiel, Germany the underlying molecular NATs and N-terminal acetyla- na Arranz, who graduated and FRIPRO programs) and the diabetes disorders, with em- and during his PhD he studied mechanisms of virulence will tion. The Arnesen group has in Biology (Biomedicine) and Norwegian Cancer Society. phasis on identifying a gener- bacterial second messenger help us better understand the revealed that NatA are impor- obtained her PhD in Physiol- al, age-related mechanism of signaling at the University of important role they play in the tant for cancer cell survival ogy at the Universidad Com- disease onset. She is currently Basel, Switzerland. He then fitness of this pathogen. Ulti- and has also demonstrated a plutense de Madrid (UCM), SIMONA CHERA building up her research group moved to Harvard Medical mately, this knowledge might link between NatA and can- Spain. Under the supervision Group Leader at the University of Bergen. School, US, where he devel- contribute to the development cer cell drug sensitization. of Professor M. De la Fuente, oped an interest in next-gener- of new interventions against Furthermore, the lab recently she studied the contribution Cell fate, ageing and decay ation sequencing technologies this ancient scourge. developed the first specific of fully differentiated myeloid Simona Chera has TRUDE HELEN FLO and applied them to the study NAT-inhibitors in collaboration cells to the aging process, with her background Professor, Co-director of Vibrio cholerae infections. with Professor Paul R. Thomp- a focus on oxidation and in- from the regener- In 2015, Abel started his own THOMAS ARNESEN son (UMass). These potently flammation. Furthermore, Ar- ation field and her Research group on group as NCMM Young Associ- Group Leader target specific NAT-enzymes ranz also became interested in main interest is host-pathogen interactions ate Investigator at the Uni- and are currently being devel- the neuro-endocrine regulation characterizing the in mycobacterial and HIV versity of Tromsø. He is also Protein N-terminal acetylation oped further for cellular and of the immune system during molecular mechanisms con- infection a Visiting Assistant Professor Thomas Arnesen in vivo studies for the potential this period. Arranz then moved trolling regenerative cellular Mycobacterial in Medicine at Harvard Medi- has a PhD in molec- use in cancer chemotherapy. to Fundacion Centro Nacional processes. During her PhD she infections pose a cal School. The Abel research ular biology from Moreover, the group has been de Investigaciones Cardiovas- identified and defined a novel global health chal- group is currently in its startup the Department of involved in identifying and culares (CNIC), where during level of complexity governing lenge with tuber- phase: 2 postdocs as well as 2 Molecular Biology mechanistically investigat- her first postdoc at Dr. S. Gon- the regeneration response in culosis killing more graduate students (startup and (MBI) at the Univer- ing the first genetic disorder zalez’ laboratory, she studied a classical invertebrate mod- than 1.5 million FriPro) were recently hired. sity of Bergen and did his post- caused by a NAT-mutation, the the contribution of dysregu- el-system of regeneration people each year and disease Furthermore, the group has doc at the Department of Sur- Ogden syndrome. The lethal lated Polycomb proteins in he- (Chera et al., 2010, Dev. Cell). caused by opportunistic strains funding for an additional post- gical Sciences, UiB, and at the Ogden syndrome and addition- matopoietic stem cells to both Briefly, she demonstrated is on the rise. Long treatment doc (Helse-Nord) and a shared Department of Biochemistry al cases and syndromes involv- aging and the blood malignan- that an efficient regeneration with antibiotics is required graduate student with the and Biophysics at the Univer- ing cardiac arrhythmias and cies classified as myeloprolifer- requires the apoptosis-induced and drug resistant strains are Optical Nanoscopy group at sity of Rochester, US. Arnesen intellectual disabilities caused ative neoplasms. From 2012 to compensatory proliferation emerging. The group’s primary the University of Tromsø (UiT is currently group leader of the by NAT mutations are current- 2014 she performed her second promoted by dying cells research focus is molecular Strategic Funding). N-terminal acetylation (NAT) ly being functionally studied postdoc, working in the group through a Wnt3a-dependent host defense mechanisms group at MBI. The NAT-group in the lab. Finally, the Arnesen of Dr. S. Mendez-Ferrer, where mechanism. For her postdoc- involved in fighting patho- The Infection Biology research is one of three nodes com- group is also pursuing links she uncovered the critical role toral studies, she analyzed the gens and virulence strategies group studies the molecu- prising the ProtMetD (Protein between NATs and metabolism. played by the hematopoietic cellular and molecular basis employed by mycobacteria to lar mechanisms that enable modifications, metabolism and stem cell niche in the patho- of murine pancreatic β-cell parasitize host cells. The in- pathogens to adapt to different disease) research program at genesis of these diseases. This regeneration (University of ter-connected roles of traffick- environmental conditions dur- MBI and the group is using LORENA ARRANZ work was published in Nature Geneva, Switzerland). During ing, compartmentalized PRR ing infection and transmission. eukaryotic model systems like Group Leader and received an Achievement this work she generated a new signaling and iron metabolism The Abel lab primarily focuses Saccharomyces cerevisiae, mam- Award at the congress of the transgenic model of inducible, for mycobacterial survival on Vibrio cholerae, the causative malian cell cultures and Danio Stem Cell Aging and Cancer American Society of Hematolo- specific and totalβ -cell loss, make these processes attrac- agent of the severe diarrheal rerio, combined with in vitro The Stem Cell Aging gy (ASH) in 2013. In November termed RIP-DTR. By coupling tive targets for drug develop- disease cholera and studies biochemical approaches. and Cancer (SAC) 2014, Lorena joined the De- this β-cell ablation model with ment and are currently inves- how this organism senses and The Arnesen lab is focusing research group partment of Medical Biology at genetic lineage-tracing tools tigated in our lab both in the survives the radically different on the molecular and cellular performs research the University of Tromsø (UiT) and transgenic setups allow- host and in the pathogen. The conditions it encounters during biology of protein N-terminal within the patho- as Group Leader and NCMM ing the modulation of gene group is currently also stud- the passage through the host acetylation, a major protein physiology of stem Young Associate Investigator, expression, they were the first ying innate properties of the
44 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 45 NCMM ASSOCIATE INVESTIGATORS AND YOUNG ASSOCIATE INVESTIGATORS
T-cell responses to HIV and at Oslo University Hospital, SIVER MOESTUE mycobacteria. T-cells express Rikshospitalet. In addition to Assoc. Professor PRRs and respond to microbial Melum, the group consists of ligands with cytokine produc- one postdoc, four PhD-stu- MR Cancer Group tion. The significance of this dents as well as one tech- Siver Moestue is a in disease and also in vaccine nician. The group is part of member of the MR design is currently not under- the Norwegian PSC research Cancer Group at the stood and is something Flo center located at the Research Norwegian Univer- and colleagues are interested Institute for Internal Medicine sity for Science and in. This basic research strat- (RIIM) at Oslo University Hos- Technology (NTNU) egy may contribute to reveal pital, Rikshospitalet. and his research focuses on new therapeutic targets and cancer metabolism. Moestue vaccine development. The research interests of the also works with functional MR group range from large-scale imaging for studies of tumor The research group is led by genetic studies (genome-wide microenvironment and clinical Professor Trude H. Flo and association and deep sequenc- PET/MR imaging in prostate inhibitors in endocrine resist- the University of Oslo while arrays, mRNA arrays, miRNA includes 2 more research ing studies) to immunological cancer. ant breast cancer. His research continuing her education arrays), RNA seq, DNA seq scientists, 4 post docs, 4PhD mouse models for bile duct group, currently comprising 2 in pathology. She was also and in situ analyses and has students, 2 medical research inflammation. The genetic risk From 2002-2007 Moestue postdocs and 3 PhD students, trained in molecular pathology trans-disciplinary collabora- students and master students. factors so far uncovered in worked at GE Healthcare’s has also developed tools for at the Department of Pathology tions, including bioinformati- The group has developed ex- the genetic studies in PSC are Preclinical Biology unit in Oslo, studying the relationship at the Oslo University Hospi- cians and biostatisticians. pertise, methods and tools to mainly related to the function developing novel contrast between metastatic potential, tal (OUS) by Prof. Jan Delabie. Finally, Russnes is dedicated study HIV and mycobacteria of the immune system and the agents for medical imaging (ul- tumor microenvironment and Except from an 18 months in facilitating clinical trials and the host innate and adap- group is therefore increasing trasound, MRI and PET). After metabolism in cancer using 13C post-doc period in Prof. Korne- in need of molecular based tive immune defenses both their efforts in developing im- relocating to Trondheim in NMR tracer flux studies. lia Polyak’s group at Dana-Far- diagnostics and optimizing in vitro in human primary munologically driven models 2008, he did his PhD working Moreover, Moestue is responsi- ber Cancer Institute/Harvard study design and sampling to cells and in vivo in mice. The of bile duct inflammation. The on molecular characterization ble for the preclinical projects Medical School, Boston, USA be feasible for translational group has strains of Mtb, M. work in these mouse models of breast cancer subtypes. in the MR Cancer Group, and the main part of her research research. avium and M. smegmatis avail- focuses on understanding the In collaboration with Prof. therefore also works with vari- activity has been within the able with fluorescence and immunological process regu- Anne-Lise Børresen-Dale and ous MR imaging techniques, in Børresen-Dale research group luciferase and performs live lating inflammation in the bile Prof. Gunhild Mælandsmo particular DCE-MRI, for studies at the Department of Genetics, PIA ABEL ZUR imaging of Mtb and HIV infec- ducts. The group has for the (OUS Radiumhospitalet), he of tumor vasculature and ad- Institute for Cancer Research WIESCH tions. Furthermore, they have first time demonstrated that demonstrated novel associa- vanced diffusion-weighted MRI (ICR), OUS. From 2015 Russnes Group Leader, Visiting transposon mutant libraries the cholangiocytes lining the tions between the molecular for improved diagnostic imag- entered a joint position as a Assistant Professor with more than 150 000 mu- biliary tree in both mice and background of breast cancers ing and therapy monitoring. researcher at Department of tants in M. smegmatis, M. avium humans can present antigens and their metabolic profiles. Genetics, ICR (50%) and as a Systems Pharmacology and Mtb available. Finally, to natural killer T cells (NKT). This knowledge was further senior consultant at Depart- Dr. Abel zur the group also pioneer the To expand these findings to in expanded in his postdoc peri- HEGE G. RUSSNES ment of Pathology (50%) at Wiesch studied use of FIB-SEM to establish vivo mouse models the group od, where he used MR spec- MD, Researcher, Head OUS. Russnes is since January biochemistry and nanoscale resolution imaging has developed a novel mouse troscopy to identify metabolic of Section for Molecular 2016 Head of the Section for molecular biology of intracellular mycobacterial model where they introduce biomarkers to treatment with Pathology Molecular Pathology. at the University infections. a NKT activating antigen into PI3K inhibitors. During this Kiel, Germany, the biliary tree using surgical period they developed novel Genomic alterations in Russnes has a project group Griffith University, Australia techniques with development 31P MRS protocols for therapy breast cancer with impact which today consists of one and University Basel, Switzer- ESPEN MELUM of cholangitis. Furthermore, monitoring, with high poten- on prognosis, therapy PhD student, two post-docs, land. After passing her MSc Group Leader / Senior to expand the knowledge on tial for clinical translation. prediction and clinical fol- two master students and three with distinction, she worked Scientist the importance of NKT cells low-up engineers (http://ous-research. at Roche Diagnostics and was we are investigating lipid In 2014, Moestue was award- During medical no/russnes/). an intern at WHO. She did her Experimental Hepatology accumulation as a mean to ed a FRIPRO Young Talented school Hege G. PhD in Theoretical Biology at Espen Melum is regulate the function of NKT Researcher grant, in a project Russmes was The main focus of the group ETH Zurich and received the currently leading cells during development aiming to describe the met- involved in cancer is breast cancer research ETH Medal for an outstanding the research group and activation which can abolic plasticity shown by research at The with ongoing projects in the PhD thesis. During her work as Experimental potentially have translational cancer cells following treat- Norwegian Ra- following areas: 1) Molecular Research Fellow at Harvard and Hepatology which implications. ment with drugs targeting key diumhospital supervised by classification, 2) Intra tumor Yale, she held several career focuses on transla- energy metabolism pathways. Prof. Jahn M. Nesland, Prof. heterogeneity, 3) Circulating development grants from the tional research relevant to the In collaboration with Prof. Anne-Lise Børresen-Dale and biomarkers, 4) Tumor evolu- German Academic Exchange chronic liver disease primary Ian Mills (NCMM and Univ. of Prof. Ragnhild Lothe. Later, tion and 5) Molecular markers Service and the Swiss National sclerosing cholangitis (PSC). Belfast) and Prof. Mælands- after completing 2,5 years in clinical trials. The group Science Foundation. In 2015, In addition, he is training mo, Moestue is now studying training in pathology, Russnes uses a multitude of methods Dr. Abel zur Wiesch became a in clinical gastroenterology metabolic responses to OGT entered the PhD program at such as microarrays (SNP NCMM Associate Investigator
46 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 47 NCMM ASSOCIATE INVESTIGATORS AND YOUNG ASSOCIATE INVESTIGATORS and joined the University of Tromsø as a tenure track Asso- IN MEMORY OF HELGA BIRGITTE SALVESEN ciate Professor. She also holds (1963-2016) Research Highlights a visiting professorship at Yale School of Public Health, where at the Faculty of Medicine she spends 20% of her time and and Dentistry, UiB. In 2015, employs one postdoc. Helga Salvesen received the Health West Research and The work in Tromsø is sup- Innovation Award for her PhD fellow and MD Simer Bains presented data on aspirin treatment ported by a statistician. In outstanding work related to addition, one postdoc and personalized treatment of and colorectal cancer at the 2015 ASCO Conference PhD-student will start in the gynecological cancer. She spring 2016. The group will was also elected member of The 2015 American Society of Clinical Oncology use theoretical models in close the Norwegian Academy of (ASCO) Meeting took place in Chicago on May collaboration with experimen- Science and Letters in 2015. 29 - June 2. This annual meeting brings together talists and clinicians to explore around 30 000 oncology professionals from how we could use both with- Helga Salvesen was a spe- around the world to hear the latest news from in-host and population-wide Helga Salvesen was appoint- cialist in gynecology and the world of cancerology. NCMM PhD fellow drug treatment strategies to ed NCMM Associate Investi- obstetrics and during her ca- Simer Bains gave an oral presentation entitled minimize human morbidity gator in an open call in 2011 reer she had several research “Impact of aspirin as secondary prevention in an and mortality. The focus of and was reappointed in 2015. stays abroad, including the unselected cohort of 23 162 patients with colorectal the research is rationalizing Her knowledge, passion for Dana Farber Cancer Institute cancer: A population-based study” for an audinence antibiotic treatment by bridg- science and drive made her at Harvard Medical School, of almost 5000 people. She was the only ing the gap between intra- a key contributor to building Broad Institute MIT as well Norwegian speaker at the meeting and her talk cellular reaction kinetics and up a national translation- as the University of Chicago. was mentioned both in national media such as by bacterial population dynamics al network in molecular In particular, she focused Dagens Medisin: http://www.dagensmedisin.no/ Simer J. Bains (MD, PhD) to improve dosing regimens medicine in Norway. Both on developing molecular artikler/2015/05/31/asco-debuterte-foran-5000/ Photo : Lisbeth Nilsen, Dagens Medisin in tuberculosis therapy. The the NCMM Centre Director biology tools in her studies of and echoed in international discussion and group links single cell analy- and NCMM group leader gynecological cancers. Helga media e.g. in the Medscape note by Professor and colorectal cancer-specific survival (CSS) in ses to clinical studies and are Toni Hurtado enjoyed good Salvesen published more David Kerr, University of Oxford: http://www. CRC patients and found that aspirin exposure funded by the Bill & Melin- and fruitful collaborations than 130 scientific papers medscape.com/viewarticle/845146. after the diagnosis of CRC was independently da Gates foundation. These with her and her colleagues. and has supervised a number associated with improved CCS as well as OS. models are also employed to It was with shock and great of PhD fellows. Worldwide, 1.3 million patients are diagnosed develop new extended release sadness we received the mes- with colorectal cancer (CRC) every year and The study was recently published in the Journal technologies together with sage that Helga passed away Although Helga was an Norway, with a population of 5.1 million, has an of Clinical Oncology revealing that this patient gastroenterologists at Harvard very unexpectedly in January impressive clinician and a annual incidence of approximately 4000 cases. group has a 15% improved cancer-specific survival Medical School and MIT. In 2016. brilliant cancer researcher, Evidence from randomized controlled trials and and 5% improved overall survival compared to collaboration with researchers what was most impressive experimental and observational studies indicate those not using aspirin. Furthermore, patients at the Department for Systems Helga Salvesen was a full- about her was her personal that aspirin and non-steroid anti-inflammatory using aspirin both before and after diagnosis had Pharmacology, Harvard Med- time surgeon at Haukeland warmth. She was a dedicated drugs (NSAIDS) can decrease the incidence and an even further improved CSS and OS. Given the ical School, Abel zur Wiesch University Hospital who also and caring physician and mortality of CRC, when used prior to diagnosis. facts that aspirin would be a cheap treatment explores how resistance mech- ran a very active research researcher and became a However, use of aspirin as primary prevention in with few side effects these findings may have anisms affect bacterial suscep- lab. She was a prominent role model for many young the general public is debated as aspirin-induced potential value for the many patients diagnosed tibility. In addition, the team Professor at the University of scientists and doctors. She gastric- and cerebral hemorrhage impact the and treated for colorectal cancer every year. recently developed a method Bergen (UiB) and was in the always had the patients’ best risk-benefit assessment. In contrast, secondary The full article “Aspirin as Secondary Prevention to infer pathogen population forefront internationally in interests at heart. NCMM prevention in patients already diagnosed with in Patients with Colorectal Cancer – An Unselected dynamics in collaboration with the research field of gyne- feels honored that Helga CRC may offer more advantage with respect to Population-Based Study” is being published in the Sören Abel and works on resis- cological cancers. Together Salvesen took the time to be risk of recurrence as well as a different risk- Journal of Clinical Oncology in May 2016. tance evolution in nosocomial with her colleagues, she was part of the NCMM Associate versus-benefit profile. infections and tuberculosis. responsible for several scien- Investigator network and we Furthermore, a new multicenter study is being tific breakthroughs that have value our collaborations over At the ASCO meeting Simer Bains presented initiated focusing on aspirin effects on patients contributed to the discovery the years. data from a large cancer registry study coupling suffering from colorectal cancer that have also of new potential treatment data from the Norwegian Cancer Registry surgically removed liver metastases. This study targets and markers for indi- and the Norwegian Prescription Database. will be performed in collaboration with Oslo vidualizing gynecologic can- This population-based, retrospective cohort University Hospital (Bjørn Atle Bjørnbeth, Sheraz cer care. In addition, she was study included 23 162 patients diagnosed with Yaqub) as well as with colleagues in Stavanger, the Co-Director of Centre for colorectal cancer in Norway in the period 2004- Bergen, Trondheim and Tromsø. Cancer Biomarkers (CCBIO), 2011, including 6.102 regular aspirin-users. a center of excellence (CoE) Bains and her colleagues assessed whether use of aspirin can influence overall survival (OS)
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Targeting metabolic feedback cancer treatments (eg. Radiotherapy) and also to The bacteria are shown in enhance the therapeutic impact of repurposed, green. The multi-coloured pathways to enhance treatment area shows how the pump clinically approved therapies. responses and accelerate drug rests on the bacterial mem- brane (pink). The ‘machine’ repurposing 1. Itkonen HM, Engedal N, Babaie E, Luhr M, itself inside the membrane is Guldvik IJ, Minner S, Hohloch J, Tsourlakis shown in orange. The grey As cancers develop they acquire the ability to MC, Schlomm T, and Mills IG. UAP1 is dots are magnesium atoms. evolve rapidly to resist therapeutic stress. Over overexpressed in prostate cancer and is Photo: Jens Preben Morth, the course of the last few years we have focussed protective against inhibitors of N-linked UiO on processes that modulate stress response glycosylation. Oncogene. 2015;34(28):3744-50. signalling and the hexosamine biosynthesis 2. Itkonen HM, Gorad SS, Duveau DY, Martin SE, pathway as one example. This pathway utilises Barkovskaya A, Bathen TF, Moestue SA, and metabolites from core metabolic processes Mills IG. Inhibition of O-GlcNAc transferase to create substrates for the modification of activity reprograms prostate cancer cell proteins to alter their stability and activity. metabolism. Oncotarget. 2016. We are collaborating with Professor Suzanne Walker’s group (Harvard Medical School) to Bacteria use their own pumps to characterise novel inhibitors of a conjugating collect magnesium enzyme, OGlcNAc tranferase (OGT) and have also studied the impact of an upstream enzyme, Magnesium is found in all living organisms UDP-N-Acetylglucosamine Pyrophosphorylase and in humans most magnesium is found in 1 (UAP1) which generates the substrate for the skeleton. We are supplied with magnesium OGT. Reducing UAP1 levels enhances the stress through our daily diet or as a supplement. response signalling to chemical stressors of the Magnesium deficiency is not common, but unfolded protein response in cells – response occurs in patients with intestinal diseases such often activated by radiotherapy and other as Crohn’s disease. These patients often have treatment modalities1. Targeting OGT sensitises to live with cramps and various rheumatic prostate cancer cells to clinically approved drugs illnesses. Other symptoms typical of magnesium such as Metformin, which impose metabolic deficiency are muscular spasms, cramps, anxiety stress on cells often by impacting in part on or abnormal heart rhythms. mitochondrial function2. Working with NCMM Young Associate Investigator Dr. Siver Mostue Morth and colleagues have recently discovered (NTNU), and his team we were able to identify that the system used by bacteria to transport alanine as a metabolite that was consumed magnesium is so sensitive that it can detect upon targeting OGT to help to maintain cell a pinch of magnesium salt in a swimming bacteria have developed a unique system to detect that apply when magnesium is identified and survival2. In addition, targeting OGT significantly pool. They have identified a nano-sized and attract magnesium. The bacteria manage to absorbed into cells. Not only in the case of upregulated the expression of an important magnesium pump and demonstrated how do this even if the amounts of magnesium in bacteria, but also in more advanced organisms. alanine metabolising enzyme, glutamic pyruvate sensitive the bacteria’s transport system is. The their environment are only minimal. In future we may be able to use this information transaminase (Alanine Aminotransferase) 2 pump was isolated in the plasma membrane to create drugs that counteract this process and (GPT2)2. By combining early-stage OGT inhibitors from E. coli. In addition to the pump itself, Magnesium is bound to several proteins within thus prevent antibiotic resistance. In addition, with a clinically approved drug, cycloserine the researchers also discovered unique lipid a cell. For example, it is used by many of the it will help us understand how bacteria protect (seromycin) which inhibits GPT2, we achieved an components, in particular cardiolipin, that assist enzymes that are involved when sugar is broken themselves against the hostile environments in enhanced cytotoxic response in prostate cancer the bacteria in this process. down into energy (glycolysis) and magnesium the human body. cells2. Cycloserine is currently used as a second- Magnesium deficiency can be deadly for bacteria. also stabilises genetic material in both humans line drug to treat tuberculosis. Future work will This has led to our own cells developing a and bacteria. The full article “The magnesium transporter A is involve further optimisation of the specificity of mechanism that removes magnesium and other activated by cardiolipin and is highly sensitive to free OGT inhibitors with a line of set to testing them metals from bacteria when they start attacking This discovery will hopefully help us to magnesium in vitro” can be found in eLife. 2016; 5: as enhancers of therapeutic response to standard us. In order to counteract this mechanism, understand some of the molecular systems e11407. doi: 10.7554/eLife.11407
50 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 51 Events 2015 September
Nordic EMBL Partnership In September the Danish node Dandrite hosted the 6th annual meeting for the Nordic EMBL Partnership for Molecular Medicine in Aarhus. More than 150 participants from all the four Nordic nodes as well as from the EMBL enjoyed two days of scientific interaction. NCMM PhD student Shixiong Wang was one of two poster award winners. The Nordic EMBL Partnership admin meeting took place in Helsinki in April February 2016 Joined the Medical Faculty, UiO The University Board decided that the Faculty of Medicine should host NCMM from April 2015. The fact that the Faculty of Medicine is now hosting NORDIC EMBL
Photo: J. Landskron, NCMM NCMM and cooperates PARTNERSHIP FOR closely with the Faculty of MOLECULAR MEDICINE Mathematics and Science March in this endeavor offers new opportunities, both SAB Visit strategically with the two The Scientific Advisory Board (SAB) visited Faculties and with more NCMM in March 2015. In addition to scientific alignment and potential for presentations and discussions with group leaders synergies at all levels. and the director as well as evaluation of a PI, the SAB also enjoyed a scientific lunch with NCMM PhD fellows and postdocs.
Photos: Dandrite and FIMM
May October National PhD courses In May group leader Preben Morth organized a one-week BioStruct PhD course Scientific Retreat entitled “Membrane Proteins, from isolation to crystals” (MBV9300BTS) at In October NCMM and NCMM. The course included both practical lab work and theoretical lessons. the Biotechnology Center organized a joint scientific NCMM also organizes a national PhD course in molecular medicine that takes retreat that took place at place every year in November (MF9120BTS). Altogether, 33 participants from Holmsbu Spa and Resort, just Norway (Oslo and Trondheim) and Finland (FIMM) attended this two-week outside Oslo. This two-day course in 2015. The course aims to give its participants insights into the event included scientific talks translational and clinical aspects of science. and discussions, a social dinner and outdoor activities.
52 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 53 King Olav Vs Prize for Cancer Research
In March 2016 the Norwegian Cancer Society announced that Professor Kjetil Taskén will receive the prestigious King Olav Vs Prize for Cancer Research for his work on immunotherapy. King Olav V’s Cancer Research Award 2016 is presented by HM King Harald V on behalf of the Norwegian Cancer Society in Oslo on 6 June.
King Olav V’s Cancer Research Award is distributed annually to scientists who have distinguished themselves through years of efforts to ensure a better life for many people and the winner receives 1 million NOK. The prize is highly valued among cancer researchers in Norway.
In the press release from the Norwegian Cancer Society it is stated that Kjetil Taskén has contributed greatly to the understanding of immune-oncology and that this research will become even more relevant in the development of next generation immunotherapy. The Secretary General of the Norwegian Cancer Society says “she is especially happy to give the prize to a researcher who works with immunotherapy, which many believe is the future of cancer treatment. Immunotherapy can contribute to a treatment that is tougher against cancer, but easier on the patient”. Professor Taskén will receive the prize at a ceremony in Gamle Festsal at the University of Oslo on 6 June 2016.
54 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 55 The panel debate on private research funding was chaired by research dean Hilde Nebb, UiO. Panel members from left: Anne Lise Ryel (The Norwe- gian Cancer Society), Johanna Olweus (OUH/ UiO), John-Bjarne Hansen (UiT), Espen Melum (OUH, UiO) and Kåre Rommetveit (Bergen Forsk- ningstiftelse, Stiftelsen Kristian Gerhard Jebsen) NCMM Network Meeting Photo: Gang Cheng, NCMM
The panel debate “Innovation in the health care sector – challenges and opportunities” was chaired by Kjetil Storvik, HSØ. Panel members from left: Ketil Widerberg (Oslo Cancer Cluster), Bjarte Reve (Nansen Neu- roscience Network), Ole Kristian Hjelstuen (Inven2), Guttorm Haraldsen (NORIN) and Agnete B. Fredriksen (Vaccibody) Photo: Johannes Landskron, NCMM
Clinical trials - implementation of per- sonalized medicine, new drugs and advanced therapeutic medicinal products (ATMPs). Panel members from left: Hans Olav Melberg (UiO), Steinar Madsen (Legemiddelverket), Else Krüger-Hagen (Novartis), Karl-Johan Malmberg (OUH/ UiO) and Per E. Lønning (UiB/Haukeland The NCMM Network Meeting was opened by Frode Vartdal, Dean at the Medical Faculty, UiO. Photo: Gang Cheng, NCMM University Hospital) Photo: Johannes Landskron, NCMM
In the fall 2015 NCMM announced the re- The first day of the meeting took place at the second day the audience was invited to several responded, revealed that the participants found appointment and new appointment of altogether Norwegian Academy of Science and Letters panel debates covering topics such as research the meeting interesting, engaging, inspiring and 22 NCMM Associate Investigators and Young whereas the second day was organized at career development at the young group leader different. NCMM will therefore aim to have an Associate Investigators (see separate section). To the Oslo Science Park and was also open to stage, new diagnostic possibilities - the road to annual network meeting to further stimulate kick of the extended network program, NCMM all NCMM staff. The first day the program personalized medicine, clinical trials, innovation interaction and collaboration between NCMM organized a network meeting that took place on included a scientific speed-dating as well as talks in the health care system as well as challenges and Associate Investigators / Young Associate 18-19 January 2016. This meeting was intended covering topics such as team building and top and benefits of large research infrastructures. Investigators and to interact with external for NCMM group leaders, newly appointed and performances, research dissemination and media stakeholders and to further position NCMM on reappointed NCMM Associate Investigators and strategy, creating an international workplace Altogether, 55 participants attended the network the national arena. Young Associate Investigators, Board members and how to understand cultural differences as meeting and an evaluation after the meeting and other stakeholders and scientific leaders. well as a debate on private research funding. The where approximately one third of the participants
56 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 57 NCMM PhD dissertations
the blood and lymphoid tissues, looking for invading microorganisms and cancer cells, also MD Simer J. Bains called antigens. T cells are activated when they MD Simer J. Bains defended recognize foreign or harmful antigens and can her thesis entitled either destroy foreign elements directly or secrete “Malignancy, Metastasis molecules that mobilize the rest of the immune and Immune Modulation – NCMM has recruited an international group of PhD fellows and currently system. It has been demonstrated that the Experimental Tumor Immune 15 PhD candidates from eight different countries are working on exciting organization of proteins and lipid components in Regulation and Observational the plasma membrane influences how effective Clinical Studies in Ovarian and projects in translational molecular medicine. In 2015 and the beginning of and precise the T cells are activated. Moltu and Colorectal Cancer” in January 2016 four NCMM PhD fellows defended their thesis. colleagues therefore investigated which proteins 2016. The work was performed in the research that are recruited to the plasma membrane upon group of Kjetil Taskén and Bains defended her activation and which proteins that are removed. thesis at the Institute of Clinical Medicine, the Such an overview is a good starting point for Medical Faculty, UiO. identifying proteins that can be manipulated in Stefan J. Barfeld crucial for rapidly dividing cancer cells, which the immune response. In her PhD work, Simer Bains focused on how Stefan J. Barfeld defended need large quantities of purines to sustain cancer develops in interaction with the body’s his thesis entitled “The proliferation. Notably, disrupting this pathway It is very important that activation of T cells is immune system. Furthermore, she focused transcriptional role of c-Myc in slowed cancer cell growth and induced a cellular tightly regulated. The immune response needs to on different treatment strategies for patients prostate cancer” in October stress response. Moreover, the impact of elevated be sensitive enough to detect damaging cancer suffering from colorectal cancer. 2015. The work was c-Myc levels on androgen receptor activity was cells but not so sensitive that the immune system Aspirin is known as a common pain reliever, a performed in the research examined. Strikingly, c-Myc overexpression attacks the body’s own cells. A T cell therefore drug used to reduce fever or as blood thinning group of Ian Mills and dysregulated androgen receptor activity and needs two signals to become fully activated. In medication used by heart patients. In an Barfeld defended his thesis suppressed a range of well-established androgen her PhD work, Moltu has used a new technology observational study, including 23 162 Norwegian at the Department of Biosciences, Faculty of receptor targets. These findings have potential (phospho-flow) that enables identification of colorectal cancer patients, Bains and colleagues Mathematics and Natural Sciences, UiO. implications for future prostate cancer patients signaling cascades inside single cells to study revealed that patients that have been treated with as they provide novel insights into the molecular how the second activation signal contributes to aspirin live significantly longer than patients that Every year, about 4,000 men die as a result of basics of the disease, which could offer treatment regulation of T cell activation. did not use aspirin. The data in this study came prostate cancer in Norway alone. Decades of alternatives to current therapies. from the Norwegian Cancer Registry and the research have improved detection and treatment Some patients with colorectal cancer secrete Norwegian Prescription Database and included options but nonetheless, prostate cancer often Kristine Moltu substances that could prevent activation of T all patients diagnosed with colorectal cancer remains a fatal disease. Dysregulation of the Kristine Moltu defended cells and thus elimination of the cancer cells. in Norway in the period 2004-2011. This is an androgen receptor, a testosterone-binding her thesis entitled “Signal Moltu has therefore examined which T cell interesting finding since aspirin is an inexpensive protein that controls cell proliferation, has been network analysis of T cell activation signals that are inhibited in colorectal drug with few side effects. This information could identified as the main cause and driver ofthe activation – in human T cancer patients compared to healthy blood therefor potentially benefit the 4000 patients that disease. However, a range of other proteins have cells from blood donors and donors. Insight in these differences could become are diagnosed with colorectal cancer in Norway been shown to play vital roles in prostate cancer. patients with colorectal valuable in the development of future cancer every year. Furthermore, Bains and colleagues Amongst these, c-Myc is a factor that has been cancer” at the Department therapies. demonstrated that colon cancer patients with extensively studied in various cancers, especially of Biosciences, Faculty of liver metastases can obtain the same survival lymphomas. Surprisingly, the contribution Mathematics and Natural rate as patients with only localized disease if of c-Myc to prostate cancer development Sciences in December 2015. The work was the metastases are treated as aggressively as the and androgen receptor activity has not been performed in the research group of Kjetil Taskén. original tumor, using different surgical methods thoroughly examined yet. as well as interventions. Both studies support In her PhD work, Kristine Moltu studied different previous work and may contribute to change the In his PhD work, Stefan J. Barfeld identified mechanisms that regulate T cell activation treatment practice in the future. c-Myc to be the driver of a variety of supporting both in healthy blood donors and in cancer metabolic pathways in prostate cancer, including patients. T cells play an important role in the In addition to the two mentioned studies, Bains purine de novo biosynthesis. This pathway is adaptive immune system and circulate through examined immune cells from healthy blood
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donors and from patients with ovarian cancer the interaction with its ligand estrogen, ER binds to identify specific properties and functions the chromatin in the nucleus, where it activates of regulatory T cells (Tregs). This cell type can a specific transcriptional program resulting in cell modulate the immune system and is important proliferation. Decades of research have improved to maintain tolerance to self-antigens. However, our knowledge of ER functions and prompted in connection with cancer, it is not an advantage the development of inhibitors commonly used in to have too many Tregs as they can prevent the breast cancer therapy. Moreover, recent studies body’s own immune system to fight the disease. have characterized a new class of transcription Characterizing and understanding these cells may factors, named ER cooperating factors, which therefore be important to be able to develop new tightly modulate ER mediated transcription. cancer treatments in the future. Furthermore, Alterations in the functions of these factors and of Bains and colleagues demonstrated that the their chromatin interactions can affect ER activity immediate surroundings of the ovarian cancer and breast cancer outcome. tumor inhibit the body’s immune system directly. In particular, a specific protein was identified Elisa Fiorito’s PhD work aimed at elucidating that is being secreted into the environment the functions of ER cooperating factors in surrounding the tumor and that down-regulates breast cancer cells. By employing genomic the immune system. methods, this study shed light on the molecular mechanism through which a common genetic Elisa Fiorito variant influences ER-positive breast cancer risk. Elisa Fiorito has been a PhD Moreover, Fiorito showed that the transcription fellow in the research group factor CTCF can repress a subset of genes related of Antoni Hurtado and to poor prognosis breast cancer by influencing defended her thesis entitled the formation of long-range chromatin “Study of the role of CTCF and interactions. In addition, Fiorito contributed to FOXA1 in breast cancer” in the study of FOXA1’s role in the activation of April 2016 at the Department genes promoting breast cancer aggressiveness of Biosciences, Faculty of and estrogen-independent cell growth. Mathematics and Natural Sciences, UiO. Altogether, these findings highlight the importance Breast cancer is a disease characterized by of cooperating transcription factors and open aberrant growth of the mammary epithelial cells. clinical perspectives on the prediction of breast Its outcome can be affected by specific genetic cancer outcome. Moreover, the development components and by the activity of proteins of drugs able to modulate the functions of these influencing cell proliferation and death. In her factors might be crucial to overcome anti-estrogen PhD work, Elisa Fiorito aimed to understand resistance and prevent breast cancer progression. the role of a specific genetic variant and of the transcription factors CTCF and FOXA1 in breast cancer.
Breast cancer is the most common female malignancy in the world, representing the first cause of cancer death among women. In particular, this disease is characterized by uncontrolled proliferation and migration of mammary epithelial cells. Clinical studies have shown that 70% of breast cancer cases express Estrogen Receptor α (ER), which is the main driver of cell proliferation. Upon
60 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 61 Chair R. A. Lothe
“In 2015 NCMM has under the excellent leadership of Director Taskén, strengthened its national position. After a truly competitive selection, new NCMM Associate Investi- gators were appointed, and in January this year a two day network meeting gathered young and senior Associate Investigators as well as other collaborators for stimulating
Chair of the NCMM Board, Ragnhild A. Lothe in dialogue with NCMM Director Kjetil Taskén discussions and laying the ground for new collaborative initiatives.
NCMM Board Recently, Magnar Bjørås, Ole Sejersted and Terje Espe- vik completed their work as members of the Board. “We The NCMM Board is responsible for, in BOARD MEMBERS: are most grateful for your important contributions to the collaboration with the Director, the Centre’s overall coordination and progress. The Board Chair: Board’s work”. We also welcome the new appointed steers and supervises NCMM’s activities and • Professor Ragnhild A. Lothe, Oslo University finances and does also approve the Center’s Hospital (OUH) and University of Oslo (UiO) Board members Per Morten Sandset, Maria Perander and strategic plans, objectives and budget. The Board’s decisions contribute to promote Members: Jens Petter Berg, as well as deputy member Hilde Nilsen. excellence in the Centre’s recruitments, research, • Professor Jan G. Bjålie, Faculty of Medicine, collaborations and translational value. The UiO The new Board serves as a joint board for the NCMM and Board consists of the Chair and five members • Professor Finn-Eirik Johansen, Faculty of the Biotechnology Centre. In line with the recommenda- representing NCMM’s host the University of Mathematics and Natural Sciences, UiO Oslo and the consortium partner Health South- • Director Research and Innovation Per Morten tions from both Scientific Advisory Board, the Board also East Regional Health Authority (HSE) as well as Sandset, South-Eastern Norway Regional a national representative. The Medical Faculty at Health Authority (HSE) supports the merge of the two Centres. We are pleased UiO in February 2016 appointed a joint Board for • Professor Jens Petter Berg, Oslo University NCMM and the Biotechnology Centre of Oslo for Hospital that the owners are positive to a merge and we foresee a the period 2016-2018. • Maria Perander, UiT The Arctic University of Norway (national representative) formal decision in the near future. Independent of the out-
Deputy Members: come of the decision, the Board will continuously work in • Professor Hilde Nilsen, Faculty of Medicine, UiO and Akershus University HospitalHead of the best interest of the Centers and their owners” Research Øystein Krüger, Dept. of Research and Innovation, South-Eastern Norway Regional Health Authority (HSE)
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MEMBERS OF THE SCIENTIFIC ADVISORY BOARD Scientific The Scientific Advisory Board consists of six internationally renowned scientists:
Professor Leif Groop (Chair) Advisory Head of Lund University Diabetes Centre Department of Endocrinology Clinical Sciences Malmø Board (SAB) Lund University, Sweden Professor Erich Nigg Director of Biozentrum The NCMM Scientific Advisory Board (SAB) Basel, Switzerland was first appointed in 2011 and from 2015 the SAB was appointed as a joint board for NCMM Professor Richard Treisman and the Biotechnology Centre of Oslo. The Director of CRUK London Research Institute main mission of the SAB is to offer academic Lincoln’s Inn Fields Laboratories and strategic advice as well as benchmark London, UK the performance of the groups and Centre internationally. To access recent progress and Dr. Alvis Brazma future strategies, the SAB has therefore decided EMBL Senior Scientist & Senior Team Leader to meet with NCMM core members every 12-24 EMBL-EBI Hinxton months and the fourth site-visit took place in Cambridge, UK March 2015. The next visit is scheduled for the fall 2016. Professor Margaret Frame Epidemiology Edinburgh Cancer Research Centre Edinburgh, UK
Professor Nazneen Rahman Head of the Division of Genetics and Epidemiology Institute of Cancer Research London, UK
64 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 65 NCMM Funding
Funding statistics The NCMM core funding in the first five- NCMM extramural funding in the form of grants year period was 27 million Norwegian kroner to the group leaders and other competitive mNOK (mNOK) per year from the 3 consortia partners funding has increased steadily from 7 mNOK 50 UiO, the Research Council of Norway (RCN) and in 2010 to 43 mNOK in 2014. In 2015 NCMM The illustrated funding overview Health SouthEast (HSE). Core funding at the reached 42 mNOK in annual grants. This includes includes NCMM groups, including same level was also secured for the interim year grants from the Research Council of Norway, the that of the Director from 2011. The 40 2014. A midterm evaluation was carried out by Norwegian Cancer Society, Health SouthEast, , 2016 data are based on accounts an external, international committee in 2013. competitive grants at UiO, European Commission for the first quarter as well as on After the successful evaluation, NCMM is now and private foundations and organizations budget numbers for the rest of 30 set with funding for the period 2015-19. In this such as the Lundbeck Foundation, Novo Nordic 2016. period NCMM’s partners have committed to fund Foundation, KG Jebsen Centres, Movember and the Centre with 31 million Norwegian kroner per others. Extramural funding for 2016 is so far 20 year. Including transferred funds, NCMM spent stipulated to 35 mNOK. This decrease compared 26 mNOK in 2015. This was less than budgeted to the last couple of years is a result of two and due to delays in recruitment of a new research groups rotating out of the Centre in 10 research group. For 2016 NCMM has a budget the period 2015-2016. A new research group is aiming for balance and plans to spend 37 mNOK. being established from mid-2016 and in addition For the period 2015-2019 we stipulate the NCMM a second group will be recruited. We therefore 0 Extramural Funding annual core budget expenses to be in the order of expect the amount of extramural funding to 2010 2011 2012 2013 2014 2015 2016 Centre Funding 35-38 mNOK (2015-value) with the present level increase again from 2017. of activity and including transferred funds.
NCMM Core Extramural Funding Estimated Extramural Funding Sources 2015 Sources 2015 Funding Sources 2016
4% 5% 4% 5% 4% 5% 4% 5% 6% 6% 23% 23% 8% 8%
35% 35% 37% 37% 18% 37% 18% 37% 18% 18%
12% 12% 12% 12% 42% 42% 17% 17% 17% 17%
UiO RCN HSE UiO RCNRCN UiO HSEHSE The Norwegian Cancer Society Other national granRCtsN EUUiO OHthSeEr InternThaeti oNnaorlw gerangiatns Cancer Society Other national grants EU Other International grants
The 2016 overview is an estimate of extramural funding sources based on budget and on secured grants.
66 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 67 Staerk J, Constantinescu S, Smith SO (2015). J Integration of copy number and transcriptomics Biol Chem. 291(6):2974-87. provides risk stratification in prostate cancer: A NCMM-Affiliated discovery and validation cohort study. Ross-Adams H, doi: 10.1074/jbc.M115.696534 Lamb AD, Dunning MJ, Halim S, Lindberg J, Massie CM, Egevad LA, Russel R, Ramos-Montoya A, Targeting tuberculosis and HIV infection-specific Vowler SL, Sharma NL, Kay J, Whitaker H, Clark J, Publications regulatory T cells with MEK/ERK signaling pathway Hurst R, Gnanapragasam VJ, Shah NC, Warren AY, inhibitors. Lieske NV, Tonby K, Kvale D, Dyrhol-Riise Cooper CS, Lynch AG, Stark R, Mills IG, Gronberg AM, Taskén K (2016). PLoS One 10(11):e0141903. H, Neal DE (2015). EBioMedicine 2(9):1133-44. doi: doi: 10.1371/journal.pone.0141903 10.1016/j.ebiom.2015.07.017
Slug-dependent upregulation of L1CAM is responsible Monitoring regulatory T cells in clinical samples: NCMM publications from 2015 Benzo[a]pyrene-induced nitric oxide production for the increased invasion potential of pancreatic cancer consensus on an essential marker set and gating Abundant genetic overlap between blood lipids acts as a survival signal targeting mitochondrial cells following long-term 5-FU treatment. Lund K, strategy for regulatory T cell analysis by flow and immune-mediated diseases indicates shared membrane potential. Hardonniere K, Huc L, Dembinski JL, Solberg N, Urbanucci A, Mills IG, cytometry. Santegoets SJAM, Dijkgraaf EM, molecular genetic mechanisms. Andreassen OA, Podechard N, Fernier M, Tekpli X, Gallais Krauss S (2015). PLoS One 10(4):e0123684. doi: Battaglia A, Beckhove P, Britten CM, Gallimore A, Desikan RS, Wang Y, Thompson WK, Schork AJ, I, Sergent O, Lagadic-Gossmann D (2015). 10.1371/journal.pone.0123684 Godkin A, Gouttefangeas C, de Gruijl TD, Koenen Zuber V, Doncheva NT, Ellinghaus E, Albrecht M, Toxicol In Vitro 29(7):1597-608. doi: 10.1016/j. HJPM, Scheffold A, Shevach EM, Staats J, Tasken Mattingsdal M, Franke A, Lie BA, Mills IG, Aukrust tiv.2015.06.010 The androgen receptor controls expression of the K, Whiteside TL, Kroep JR, Welters MJP, van der P, McEvoy LK, Djurovic S, Karlsen TH, Dale A cancerassociated sTn antigen and cell adhesion through Burg SH (2015). Cancer Immunol Immunother (2015). PLoS ONE. 10(4):e0123057. A Loss-of-Function Variant in a Minor Isoform induction of ST6GalNAc1 in prostate cancer. Munkley 64(10):1271-86. doi: 10.1007/s00262-015-1729-x doi: 10.1371/journal.pone.0123057 of ANK3 Protects Against Bipolar Disorder and J, Oltean S, Vodak D, Wilson BT, Livermore KE, Schizophrenia. Hughes T, Hansson LJA, Sønderby Zhou Y, Star E, Floros VI, Johannessen B, Knight B, Glucocorticoid receptor and Klf4 co-regulate anti- Myc-dependent purine biosynthesis affects nucleolar IE, Athanasiu L, Zuber V, Tesli MS, Song J; McCullagh P, McGrath J, Crundwell M, Skotheim inflammatory genes in keratinocytes. Sevilla LM, stress and therapy response in prostate cancer. Barfeld Hultman CM, Bergen SE, Landen M, Melle RI, Robson CN, Leung HY, Harries LW, Rajan P, Latorre V, Carceller E, Boix J, Vodak D, Mills IG, S, Fazli L, Persson M, Marjavaara L, Urbanucci A, I, Andreassen OA, Djurovic S (2015). Biol Mills IG, Elliott DJ (2015). Oncotarget 6(33):34358- Pérez P (2015). Mol Cell Endocrinol 412:281-9. doi: Kaukoniemi KM, Rennie PS, Ceder Y, Chabes A, Psychiatry 11. pii: S0006-3223(15)00859-8. doi: 74. doi: 10.18632/oncotarget.6024 10.1016/j.mce.2015.05.015 Visakorpi T, Mills IG (2015). Oncotarget 6(14):12587- 10.1016/j.biopsych.2015.09.021 602. Maintaining a Healthy Balance: Targeting TERT to The Early Effects of Rapid Androgen Deprivation on CIP2A is a candidate therapeutic target in clinically Stem Benign Prostatic Hyperplasia. Pickard A, Mills Human Prostate Cancer. Shaw GL, Whitaker H, A differential protein solubility approach for the challenging prostate cancer cell populations. IG (2015). Eur Urol 69(4):555-6. doi: 10.1016/j. Cocoran M, Dunning MJ, Luxton H, Kay J, Massie depletion of highly abundant proteins in plasma Khanna A, Rane JK, Kivinummi KK, Urbanucci eururo.2015.10.028 CE, Miller JL, Lamb AD, Ross-Adams H, Russel using ammonium sulfate. Bollineni RC, Guldvik A, Helenius MA, Tolonen TT, Saramäki OR, R, Nelson AW, Eldridge MD, Lynch AG, Ramos- IJ, Grönberg H, Wiklund F, Mills IG, Thiede B Latonen L, Manni V, Pimanda JE, Maitland N J, Anchored PKA as a gatekeeper for gap junctions. Montoya A, Mills IG, Taylor AE, Arlt W, Shah N, (2015). The Analyst 140(24):8109-17. doi: 10.1039/ Westermarck J, Visakorpi T (2015). Oncotarget Pidoux G, Taskén K (2015). Commun Integr Biol Warren AY, Neal DE (2015). Eur Urol pii: S0302- c5an01560j 14: 6(23):19661-70. 8(4):e1057361. doi:10.1080/19420889.2015.1057361 2838(15)01076-3. doi: 10.1016/j.eururo.2015.10.042
Targeting protein-protein interactions in complexes Activated regulatory and memory T-cells accumulate Targeting of type I protein kinase A to lipid rafts Divergent androgen regulation of unfolded protein organized by A kinase anchoring proteins. Calejo AI, in malignant ascites from ovarian carcinoma is required for platelet inhibition by the 3,5-cyclic response pathways drives prostate cancer. Sheng X, Taskén K (2015). Frontiers in Pharmacology 6:192. patients. Landskron J, Helland Ø, Torgersen KM, adenosine monophosphate-signaling pathway. J Arnoldussen YJ, Storm ML, Tesikova M, Nenseth doi: 10.3389/fphar.2015.00192 Aandahl EM, Gjertsen BT, Bjørge L, Taskén K Thromb Haemost 13(9):1721-34. doi: 10.1111/ HZ, Zhao S, Fazli L, Rennie PS, Risberg BÅ, Wæhre (2015). Cancer Immunology and Immunotherapy jth.13042 H, Danielsen HE, Mills IG, Jin Y, Hotamisligil GS, Dynamics of ionic shifts in cortical spreading depression. 64(3) s.337-347. doi: 10.1007/s00262-014-1636-6 Saatcioglu F (2015). EMBO Mol Med 7(6):788-801. Enger R, Wannan T, Vindedal GF, Jensen V, Helm P, Genetic Sharing with Cardiovascular Disease Risk doi: 10.15252/emmm.201404509 Sprengel R, Looger LL, Nagelhus EA (2015). Cerebral Identifying Novel Gene Variants in Coronary Factors and Diabetes Reveals Novel Bone Mineral Cortex 25(11) 4469-4476. doi: 10.1093/cercor/ Artery Disease and Shared Genes with Several Density Loci. Reppe S, Wang Y, Thompson WK, Enzymatic detection and quantification assay of isatin, bhv054 Cardiovascular Risk Factors. LeBlanc M, Zuber V, McEvoy LK, Schork, AJ, Zuber Verena, LeBlanc M, a putative stress biomarker in blood. Sommer T, Kulle B, Witoelar A, Zeng L, Bettella F, Wang Y, Bettella F, Mills IG, Desikan RS, Djurovic S, Gautvik Bjerregaard-Andersen K, Simensen SM, Jensen JK, Spatiotemporal regulation of cAMP signaling controls McEvoy LK, Thompso, KW, Schork AJ, Reppe KM, Dale AM, Andreassen OA, GEFOS Consortium Jochimsen B, Riss P, Etzerodt M, Morth JP (2015). the human trophoblast fusion. Gerbaud P, Taskén K, S, Barrett-Connor E, Lighart S, Dehghan A, (2015). PLoS One 10(12):e0144531. doi: 10.1371/ ACS Chem Neurosci 6(8):1353-60. doi: 10.1021/ Pidoux G (2015). Frontiers in Pharmacology 6:202. Gautvik KM, Nelson CP, Schunkert H, Samani journal.pone.0144531 cn500346x doi: 10.3389/fphar.2015.00202 NJ, Ridker PM, Chasman DI, Aukrust P, Djurovic S, Frigessi A, Desikan RS, Dale A, Andreassen Reduced expression of aquaporins in human intestinal Genetic Markers of Human Evolution Are Enriched in MicroRNAs enrichment in GWAS of complex human OA (2015). Circ Res. 118(1):83-94. doi: 10.1161/ mucosa in early stage inflammatory bowel disease. Schizophrenia. Srinivasan S, Bettella F, Mattingsdal phenotypes. Goulart LF, Bettella F, Sønderby IE, CIRCRESAHA.115.306629 Ricanek P, Lunde LK, Frye SA, Støen M, Nygård S, M, Wang Y, Witoelar A, Schork AJ, Thompson WK, Schork AJ, Thompson KW, Mattingsdal M, Steen Morth JP, Rydning A, Vatn MH, Amiry-Moghaddam Zuber V, Winsvold BKS, Zwart JAnker, Collier DA, VM, Zuber V, Wang Y, Dale A, Andreassen OA, His499 Regulates Dimerization and Prevents M, Tønjum,T (2015). Clin Exp Gastroenterol 8:49- Desikan RS, Melle I, Werge T, Dale A, Djurovic S, Djurovic S (2015). BMC Genomics 16:304. doi: Oncogenic Activation by Asparagine Mutations of the 67. doi: 10.2147/CEG.S70119 Andreassen OA (2015). Biol Psychiatry. pii: S0006- 10.1186/s12864-015-1513-5 Human Thrombopoietin Receptor. Leroy E, Defour 3223(15)00855-0. doi: 10.1016/j.biopsych.2015 JP, Sato T, Dass S, Gryshkova V, Myat Marlar S,
68 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 69 NCMM-AFFILIATED PUBLICATIONS
Autophagic bulk sequestration of cytosolic cargo is B, Brudvik KW, Taskén K (2016). J. Clin Oncol. (In The role of glycans in the development and progression web/2015/04/Assay-Shed-Light-Potential-Stress. independent of LC3, but requires GABARAPs. Szalai P, Press) of prostate cancer. Munkley J, Mills IG (2016). html%20April%2030,%202015 Hagen LK, Sætre F, Luhr M, Sponheim M, Øverbye Nature Reviews Urology (In Press) A, Mills IG, Seglen PO, Engedal KN (2015). Exp Cell Mapping Protein–DNA Interactions Using ChIP-exo and NCMM Director featured on the facebook page Res 333(1):21-38. doi: 10.1016/j.yexcr.2015.02.003 Illumina-Based Sequencing. Barfeld S, Mills IG (2016). Glycosylation is an androgen-regulated process “Humans of Oslo Science Park” by Oslo Science Methods in Molecular Biology (In Press) essential for prostate cancer cell viability. Munkley Park, May 2015 Augmentation of Ca<sup>2+</sup> signaling J, Vodak D, Livermore KE, James K, Wilson BT, in astrocytic endfeet in the latent phase of temporal Regulatory T cells that co-express RORγt and FOXP3 Knight B, McCullagh P, McGrath J, Crundwell M, Dagens Medisin, 30 May 2015: Interview with lobe epilepsy. Szokol K, Heuser K, Tang W, Jensen are pro-inflammatory and immunosuppressive and Harries LW, Leung HY, Robson CN, Mills IG, Rajan Simer Bains, PhD fellow NCMM, about her short V, Enger R, Bedner P, Steinhäuser C, Taubøll expand in human pancreatic cancer. Chelappa S, P, Elliott DJ (2016). EBioMedicine (In Press) oral presentation at the 2015 ASCO Meeting in E, Ottersen OP, Nagelhus EA (2015). Front Cell Hugenschmidt H, Hagness M, Line PD, Labori Chicago, on a registry coupling study on secondary Neurosci 9:49. doi: 10.3389/fncel.2015.00049 KJ, Wiedsvang G, Taskén K, Aandahl EM (2016). Spleen tyrosine kinase inhibitors block CD40L induced preventive effect of aspirin in unbiased population Oncoimmunol (In Press) proliferation of chronic lymphocytic leukemia cells. of 25,000 Norwegian colorectal cancer patients. Novel steps in the autophagic-lysosomal pathway. Parente-Ribes A, Skånland SS, Bürgler S, Os Sætre F, Hagen LK, Engedal KN, Seglen PO (2015). Human regulatory T cells control TCR signaling and A, Wang D, Bogen B, Tjønnfjord GE, Taskén K, http://www.dagensmedisin.no/ FEBS J 282(11):2202-14. doi: 10.1111/febs.13268 susceptibility to suppression in CD4+ T cells. Chelappa Munthe LA (2016). Hematologica (In press) artikler/2015/05/30/billig-medisin-med-god-effekt- S, Lieske NV, Hagness M, Line PD, Taskén K, pa-tarmkreft/ Stimulation-evoked Ca2+ signals in astrocytic processes Aandahl EM (2016). J Leukoc Biol The magnesium transporter A is activated by cardiolipin at hippocampal CA3-CA1 synapses of adult mice are and is highly sensitive to free magnesium in vitro. Dagens Medisin, 30 May 2015: Simer Bains at the modulated by glutamate and ATP. Tang W, Szokol pii: jlb.2HI0815-334R. [Epub ahead of print] Subramani S, Perdreau-Dahl H, Morth JP (2016). ASCO 2015 Meeting: http://www.dagensmedisin. K, Jensen V, Enger R, Trivedi CA, Hvalby Ø, Elife 5. pii: e11407. doi: 10.7554/eLife.11407 no/artikler/2015/05/31/asco-debuterte-foran-5000/ Helm PJ, Looger LL, Sprengel R, Nagelhus EA Inhibition of O-GlcNAc transferase activity reprograms (2015). J Neurosci 35(7):3016-21. doi: 10.1523/ prostate cancer cell metabolism. Itkonen HM, Gorad Gene regulatory mechanisms underpinning prostate Professor David Kerr, Oxford comments on Aspirin JNEUROSCI.3319-14.2015. SS, Duveau DY, Martin SE, Barkovskaya A, Bathen cancer susceptibility. Whitington T, Gao P, Song registry study above presented at ASCO, 2015 TF, Moestue SA, Mills IG (2016). Oncotarget [Epub W, Ross-Adams H, Lamb AD, Yang Y, Svezia http://www.medscape.com/viewarticle/845146 Transplantation with livers from deceased donors ahead of print] doi: 10.18632/oncotarget.7039 I, Klevebring D, Mills IG, Karlsson R, Halim S, older than 75 years. Thorsen T, Aandahl EM, Bennet Dunning MJ, Egevad L, Warren AY, Neal DE, Best of ASCO 2015: The abstract on Aspirin W, Olausson M, Ericzon BG, Nowak G, Duraj Phosphoprotein detection by high-throughput Gronberg H, Lindberg J, Wei GH, Wiklund F (2016). registry study above presented at ASCO, 2015 F, Isoniemi H, Rasmussen A, Karlsen TH, Foss flow cytometry. Landskron J, Taskén K (2016). Nat Genet 48(4):387-97. doi: 10.1038/ng.3523. featured in run-through from meeting, Boston, A (2015). Transplantation 99(12):2534-42. doi: Methods in Molecular Biology,1355: 275-90. doi: Jul 31, Aug 1 and San Francisco, Aug 7-8. 2015, in 10.1097/TP.0000000000000728 10.1007/978-1-4939-3049-4_19 Patents filed in 2015 sessions on Gastrointestinal (Colorectal) Cancer: Prostate cancer markers and uses thereof. Inventors: http://10times.com/asco-boston-meeting and Liver transplantation with deceased ABO-incompatible Guidelines for the use and interpretation of assays Ian Mills and Ingrid J. Guldvik. US Patent http://west-boa.asco.org/program-0 donors is life-saving but associated with increased risk for monitoring autophagy (3rd edition). Klionsky DJ, Application No. 62099837. Filed: 5-January-2015. of rejection and post-transplant complications. Thorsen Abdelmohsen K, Abe A, Abedin MJ, Abeliovich BMC Medicine report from ASCO on presentation T, Dahlgren US, Aandahl EM, Grzyb K, Karlsen TH, H, Acevedo Arozena A, Adachi H, Adams CM, Press Items of Aspirin Registry Study: http://blogs. Boberg KM, Rydberg L, Naper C, Foss A, Bennet Adams PD, Adeli K, Adhihetty PJ, Adler SG, Agam Norwegian Cancer Society: brochure on biomedcentral.com/on-medicine/2015/06/02/ W (2015). Transpl Int 28(7):800-12. doi: 10.1111/ G, Agarwal R, Aghi MK, Agnello M, Agostinis P, personalized medicine sent to 600 000 households advances-insights-clinical-oncology-bmc- tri.12552. Aguilar PV, Aguirre-Ghiso J, Airoldi EM, Ait-Si- in Norway, February 2015. NCMM Director Kjetil medicine-asco-2015/ Ali S, Akematsu T, Akporiaye ET, Al-Rubeai M, Taskén main profile in the brochure. NCMM emerging publications 2016 Albaiceta GM, Albanese C, Albani D, Albert ML, Cancer Network Oncology report on presentation Choline Kinase Alpha as an Androgen Receptor Aldudo J, Algul H, Alirezaei M, Alloza I, Almasan Forskning.no – Ingrid Spilde, March 2015: of Aspirin Registry Study at ASCO 2015. http:// Chaperone and Prostate Cancer Therapeutic Target. A, Almonte-Beceril M, Alnemri ES, Alonso C, Does our immune defence become stronger after www.cancernetwork.com/asco-2015-colorectal- Asim M, Massie CE, Orafidiya F, Pértega-Gomes Altan-Bonnet N, Altieri DC, Alvarez S, et al. (2016). infections? Interview with Kjetil Taskén and Trude cancer/aspirin-may-help-survival-after-colorectal- N, Warren AY, Esmaeili M, Selth LA, Zecchini HI, Autophagy 2;12(1):1-222. Flo (NTNU): http://forskning.no/2015/02/blir- cancer-diagnosis Luko K, Qureshi A, Baridi A, Menon S, Madhu B, immunforsvaret-sterkere-etter-sykdom Escriu C, Lyons S, Vowler SL, Zecchini VR, Shaw Critical role of CD2 co-stimulation in adaptive NK Oncology Practice report on presentation of G, Hessenkemper W, Russell R, Mohammed H, cell responses revealed in NKG2C-deficient humans. Nasjonal Kreftsatsning, March 2015: Aspirin Registry Study at ASCO 2015: http:// Stefanos N, Lynch AG, Grigorenko E, D’Santos LiuL, Landskron J, Ask EH, Enqvist M, Sohlberg Klinisk kreftgenomikk – hva skal til? Panel www.oncologypractice.com/specialty-focus/ C, Taylor C, Lamb A, Sriranjan R, Yang J, Stark M, Traherne J, Hammer Q, Goodridge J, Larsson discussions with NCMM group leader gastrointestinal/single-article-page/aspirin- R, Dehm SM, Rennie PS, Carroll JS, Griffiths JR, S, Jayaraman Oei VYS, Schaffer M, Taskén K, Ian Mills: https://www.youtube.com/ vitamin-d-levels-protect-against-recurrent-crc/830 Tavaré S, Mills IG, McEwan IJ, Baniahmad A, Tilley Ljunggren HG, Romagnani C, Trowsdale J, watch?v=4xMeXIoAJ_U&feature=youtu.be f806006d64431f8fd46b72633aa26.html WD, Neal DE (2016). J Natl Cancer Inst 108(5). pii: Malmberg KJ, Béziat V (2016). Cell Reports (In djv371. Press) Nasjonal Kreftsatsning, March 2015: Klinisk HemOnc Today report on presentation of doi: 10.1093/jnci/djv371 kreftgenomikk – hva skal til? Panel discussions Aspirin Registry Study at ASCO 2015.: http:// The importance of DNA methylation in prostate with NCMM Director Kjetil Taskén: https://www. www.healio.com/hematology-oncology/ Aspirin as Secondary Prevention in 23,162 Patients with cancer development. Massie CE, Mills IG, Lynch youtube.com/watch?v=hN34wFMOG_M gastrointestinal-cancer/news/online/%7B10af7107- Colorectal Cancer - An Unselected Population-Based AG (2016). The Journal of Steroid Biochemistry and 177a-46d3-a376-a2e99ba9d965%7D/aspirin- Study. Bains SJ, Mahic M, Myklebust TÅ, Småstuen Molecular Biology (In Press) NCMM group leader Preben Morth mentioned in provides-survival-benefit-as-secondary- MC, Yaqub S, Dørum LM, Bjørnbeth BA, Møller C&EN, 30 April 2015: http://cen.acs.org/articles/93/ preventative-measure-in-colorectal-cancer
70 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 71 NCMM-AFFILIATED PUBLICATIONS
Medicine Blog – report on presentation of Aspirin tasken-at-the-university-of-oslo-awarded-king- Registry Study at ASCO 2015. http://www. olav-vs-cancer-research-award-2016/ drmsuarezmd.com/search?q=simer+bains Forskning.no, March 9, 2016: Royal Prize to Science Daily, May 2015: NCMM group leader Cancer Researcher in Oslo - http://forskning.no/ Morth and collaborators at Århus Univeristy kreft-forskningspriser/2016/03/kongelig-pris- have developed a new method with diagnostic til-kreftforsker-i-oslo potential: https://www.sciencedaily.com/ releases/2015/05/150511114427.htm OsloBy March 9, 2016: http://www.osloby.no/ nyheter/Kongelig-pris-til-kreftforsker-8387376. Dagens Næringsliv, kronikk, 7 November html 2015 (page 29): Kjetil Taskén and Odd Stok- ke Gabrielsen “Fra naturen, til verdens fat- Aftenposten, 10 March 2016, page 6: Kongelig tige - Hundretusener av liv er spart takket pris til kreftforsker. være «naturpreparater» som årets nobel- prisvinnere i medisin har oppdaget”: http:// KG Jebsen Centre for Cancer Immunothera- redir.opoint.com/index_pdf.php?url=http:// py, March 10, 2016: http://www.med.uio.no/ paper.opoint.com/%3Fid_site=21225%26id_ar- klinmed/english/research/centres/kgj-can- ticle=119231%26code=413&OpointShow- cer-immunotherapy/news-and-events/ Matches=&OpointPDFBorder=0&OpointPDFO- news/2016/jcit-scientist-kjetil-taskén-recieves- verlay=0&OpointData=758a8d3bc5ebf1e49533d- king-olav-vs.html cfdf05c77a5JmlkX3NpdGU9MjEyMjUmaW- RfYXJ0aWNsZT0xMTkyMzEmaWRfdXNl- Oslo University Hospital research pages: King cj04NTMzJmlkX2FwcGxpY2F0aW9uPTEwM- Olav V’s cancer research prize for 2016 to Kjetil DAwMDEmaWRfcGFydG5lcj0xJmxhbmc9bm8 Taskén http://www.ous-research.no/home/ous/ news/15957 Forskning.no – Ingrid Guldvik (NCMM), No- vember 2015: Oslo University Hospital blog: UiO, Faculty of Science and Mathematics, http://forskning.no/blogg/forskningssykehuset/ March 11, 2016: https://titan.uio.no/node/1404 forbedret-diagnostikk-prostatakreft-pa-vei Norwegian Inflammation Network, NORIN, Askeravisen, November 2015, nr 36, page 6: March 11, 2016: http://norinnetwork.no/blog/ “På lag med professor”. NCMM Director Taskén norin-congratulates-kjetil-taskén-receiving- featured in the newspaper in relation to giving king-olav-v-price-cancer-research-2016 http:// popular science lecture to high school students norinnetwork.no/blog/norin-congratulates- on cancer therapy (organized by Norwegian kjetil-task%C3%A9n-receiving-king-olav-v- Cancer Society). price-cancer-research-2016
Medical Faculty, news – March 2016: NCMM NRK Radio P2, Ekko, March 10, 2016, Interview group leader Preben Morth: http://www.med. with Anne Synnevåg about New data and de- uio.no/english/research/news-and-events/ velopment on stress and cancer spread through news/2016/bacteria-pumps-collect-magnesium. the lymphatic system. - https://radio.nrk.no/ html direkte/p2#start=10:04:42
The Norwegian Cancery Society, 9 March Dagbladet 23 March 2016: “En revolusjon 2016: King Olav V Price for Cancer Research i kreftbehandlingen” - http://redir.opoint. 2016 to NCMM Director Kjetil Taskén: https:// com/?key=7ABntAryxnminBHcOx8M kreftforeningen.no/aktuelt/siste-nyheter/ kong-olav-vs-kreftforskningspris-2016/
UiO Faculty of Medicine, March 9, 2016: Kjetil Tasken får Kong Olav Vs kreftforskningspris - http://www.med.uio.no/om/aktuelt/aktu- elle-saker/2016/kjetil-tasken-kreftforskning- sprisen.html
Oslo Cancer Cluster, March 9, 2016: Professor Kjetil Taskén at the University of Oslo award- ed King Olav V’s Cancer Research Award 2016 - http://occincubator.com/professor-kjetil-
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DIRECTOR AND PhD Fellows Signaling Networks in Health Scientific Officers Assistant Computational Biology and ADMINISTRATION Stefan Barfeld (until October and Disease Marianne Enger (from Signe H. Kaarstad (from March Gene Regulation Director 2015) NCMM Group Leader February 2016) 2016) NCMM Group Leader Kjetil Taskén Lisa Gerner Kjetil Taskén Jorun Solheim (until March Anthony Mathelier (from May Morten Luhr 2016) Stem Cell Group 2016) Chief Administrative Officer Paula Szalai (from January Senior Researchers Martine Schrøder (from NCMM Group Leader Elisa Bjørgo 2016) Einar Martin Aandahl February 2016) Judith Staerk Johannes Landskron Gladys Tjørhom (until IT Team Financial Officer Sigrid Skånland December 2015) Principial Engineer Dr. George Magklaras Anita Skolem Membrane Transport Group Kirsti E. Præsteng (from March Gang Cheng NCMM Group Leader Postdoctoral Fellows Administrative Officer 2015) Melaku Tadesse Human Resources Officer Jens Preben Morth Ana Isabel Costa Calejo Berit Barkley Nina Modahl Dihn-Toi Chu (from November Postdoctoral Fellow Principial Engineer 2015) Breast Cancer Group Safak Caglayan RESEARCH GROUPS Steffi Munack (until December Anna Mari Lone NCMM Group Leader Adnan Hashim Prostate Cancer Group 2015) Kristina Berg Lorvik Antoni Hurtado Artur Cieslar-Pobuda (from NCMM Group Leader Bojana Damnjanovic (from Maria-Niki Mylanokou March 2016) Ian Mills February 2016) Deepak B. T. G. Raj (from Head Engineer Ida Jonson February 2016) Siv Gilfillan Marie Rogne Head Engineers Postdoctoral Fellows Vannessa L. Wehbi Xavier Tekpli (until July 2015) Ingrid Jenny Guldvik Johannes Bauer Postdoctoral Fellow Frank Sætre Kaare Bjerregaard-Andersen PhD Fellows Venkata S. Somisetty PhD Fellows (until August 2015) Simer J. Bains (until January Sachin Kumar Singh (from Julia-Kristina Jensen Madsen- Guest Researcher Kim Langmach Hein (until 2016) June 2015) Østerbye Per O. Seglen August 2015) Stalin Chelappa Oksana Svärd Harmonie Perdreau-Dahl Aleksandra Dukić PhD Fellow Researcher Nora Lieske Elisa Fiorito Nikolai H. Engedal PhD Fellows Kristine Moltu (until December Shixiong Wang Theis Sommer 2015) Postdoctoral Fellows Saranya Subramani Ellen Østensen MSc student Harri Itkonen Torbjørn A. Lien (from March Alfonso Urbanucci MSc Students MSc students 2016) Carolina Alvadia Ida K. Myhrvold Stephanie Ruhland (from April 2016)
74 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 75 NCMM International FINLAND Personnel statistics 3% staff distribution POLAND 3% NCMM Staff CHINA Number of DENMARK 5% employees 10% 100 90
GERMANY 80
21% 70
60
50
PAKISTAN 40 UKRAINE 3% 30 UK 3% 20 3%1% 10 0 2010 2011 2012 2013 2014 2015 2016 FRANCE NCMM Staff (incl.FP) 8% NCMM Staff (excl. FP) Numbers for 2016 are estimated. The staff was reduced in 2015 due to rotation of one research group out of the center. In addition, the Founding Partner (FP) arrangement was terminated in 2015. In 2016, one research group is rotating out whereas a new group is being TURKEY established. Furthermore, a second VIETNAM 3% group leader/assistant director is PORTUGAL INDIA 3% being recruited. 5% 13%
GREECE 5% SPAIN 3% SERBIA NCMM International Staff 5% NCMM Staff according to SWITZERLAND type of employment NCMM Staff - Gender Balance 3% 2%
ITALY 5% 9% 9% 4%
6% 7% Director Group Leaders Senior Researchers 57% 43% 56% 44% 1357%% 43% Postdocs 56% 44%
26% PhD fellows Engineers Administration Norway IT International 24% Other personell
NCMM has employees from 18 countries and a foreign staff of Female 57 % (plus some nationalized among the Norwegian staff). Male
76 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 77 NCMM partnerships, collaborations & affiliations
NCMM Partners
Nordic EMBL Partnership for molecular medicine
NORDIC EMBL PARTNERSHIP FOR MOLECULAR MEDICINE
National & international collaborations
78 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2015 79
Rolf Ottesen Foto: Grafisk design: Millimeterpress Ottesen Trykk: Rolf www.ncmm.uio P.O.Box 1137 Blindern, NO-0318 Oslo, Norway Forskningsparken, Gaustadalleen 21, 0349 Oslo, Norway Millimeterpress, Terje Heiestad der ikke noe annet er skrevet er annet noe ikke der Heiestad Terje Millimeterpress,