Annual Report 2016

From disease mechanisms to clinical practice

NORDIC EMBL PARTNERSHIP FOR MOLECULAR MEDICINE Contents

Overview from the Director 4

NCMM History in Brief 6 Merger between NCMM and BiO 6 Welcome to the new Assistant Director 7

NCMM Research 8 NCMM Group Leaders 8 Group Taskén – Signalling Networks in Health and Disease 10 Group Mills – Prostate Cancer 14 Group Morth – Membrane Transport 18 Group Hurtado – Breast Cancer 22 Group Staerk – Stem Cells 26 Group Mathelier - Computational Biology and Gene Regulation 30 Group Lopez-Aviles - Cell Cycle Regulations 34 Group Esguerra – Chemical Neuroscience 38 Group Sekulic – Structural Biology and Chromatin 40 Group Gözen – Bionanotechnology and Membrane Systems 44

NCMM Associate Investigators 48

Research Collaborations 50

From Disease Mechanisms to Clinical Practice 52

Research Highlights 53

News and Events 2016 56 King Olav V Prize 2016 57 Network Meeting 2017 60

NCMM PhD Dissertations 61

NCMM Board 62

Scientific Advisory Board 64

NCMM Funding 65

NCMM-affiliated Publications and Press items 66

Core Facilities 72

Personnel 74

CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 3 An overview AN OVERVIEW FROM THE DIRECTOR from the Director

2016 saw a number of important developments for NCMM, including the merger NCMM extramural funding, in the form of grants to with the Biotechnology Centre, and the appointment of three new Group Leaders. the Group Leaders and other competitive funding, has increased steadily from 7 mNOK in 2010 to 42 mNOK in 2015. In 2016, NCMM reached 32 mNOK in extra mural NCMM Director, Professor Kjetil Taskén, answers some Hartmut Luecke, a structural biologist. He is currently grants. This slight decrease in comparison to previous questions on the highlights and developments at NCMM based at University of California, Irvine, where he is years is due to some research groups rotating out of during 2016/Q1 2017: the director of the university’s Centre for Biomembrane the Centre. Systems and a Professor of Biochemistry. Professor What were your highlights of 2016? Luecke will offi cially join NCMM in November 2017. How has the Nordic EMBL Partnership benefi ted 2016 and early 2017 was a busy, but very successful time NCMM in terms of research collaborations, for NCMM. In our seventh year, NCMM has grown and It was also a really successful year for NCMM in terms networking, and infrastructure? further built on its successes to become an even more of outputs, widening and strengthening our collabora- NCMM has been able to enjoy collaborations across the established and important presence in the European tions, and growth and consolidation of external fund- Nordic EMBL Network with all three other nodes, and molecular research world. ing. NCMM Group Leaders report 60-plus national col- there has also been a lot of collaboration between NCMM’s laborations, which just goes to show the strength and own research groups. Speakers from each Nordic EMBL For me, as Director, some highlights from 2016 breadth of molecular research taking place at NCMM, Partnership node have been invited for visits at other and Q1 2017 were: and the importance and relevance of this research on a nodes, and these visits and networking are something we national level. hope to see more of in the future. 1. The merger of NCMM and the Biotechnology Centre. This was fi rst initiated in 2016, and came fully into Our Group Leaders are also increasingly collaborating We have also been able to make great use of the var- effect at the start of 2017. The merger gives us a more with researchers all over the globe; this year 50-plus ious outstanding infrastructures offered across the robust centre, with larger scientifi c mass, and also a international collaborations have been reported. nodes, such as Chemical Biology infrastructures. A good basis with infrastructure and technology plat- separate NordForsk grant has also further helped to forms, as well as an even stronger international net- What do you see as the main areas of progress facilitate more Chemical Biology collaboration across work. NCMM will be home to 11 research groups and and success for the Nordic EMBL Partnership? the nodes. technology platforms across two branches; NCMM The Nordic EMBL Partnership is working very effectively; Translational Research and NCMM Biotechnology, the four centres continue to develop, and the attendance What are you most looking forward to known collectively as NCMM at our annual gatherings and our many other interactions in the year ahead? 2. Securing the funding of NOR-OPENSCREEN as a continue to increase. MIMS is now, as the fi rst of the four NCMM has a great set of research groups and a lot of very national infrastructure for chemical biology. Funding of centres, starting its 3rd fi ve-year funding period, while talented staff. I look forward to seeing NCMM groups 33 mNOK, headed by UiO (NCMM), and with University DANDRITE has been evaluated in its fi rst fi ve-year period, and individual researchers that have been working hard of Tromsø (UiT), SINTEF, and University of Bergen (UiB) with extension approved by the Board for a further fi ve towards well-defi ned and ambitious goals for extended as partners from 2016; and to join EU-OPENSCREEN as years. The support from NordForsk also ties the four periods of time capitalise on all their research efforts. a founding member when it is established in 2017 centres together with joint travel grants, courses, and I also look forward to seeing how the most recently 3. Norway entering EATRIS as a full member from 2016, exploitation of infrastructures across the four centres. recruited groups develop, and what directions they take. headed by NCMM and with UiO, UiB, NTNU, UiT, Lastly, I look forward also to upcoming recruitments of and all four Regional Health Authorities of Norway; Future areas of progress will include more shared posi- even newer groups to set up new research in NCMM. It is Northern, Southern and Eastern, Western, and Central, tions, and thus more collaboration and shared projects; always an exciting time in a place like NCMM. as partners. This was approved by the Research Council if we are able to launch funding for this as planned. of Norway and the Department of Health and Social Furthermore, the Partnership has formulated new joint In a more general context, I am looking forward to Services interest areas as a basis for grand challenge projects the Helsinki NMMN meeting in September, the next 4. A very successful EMBL Partnership meeting in June across two or more centres. NCMM national network meeting in January 2018, and 2016 in Heidelberg what ambitious goals we can reach for jointly at the 5. The fi rst NCMM Network Meetings in January 2016, How have translational research studies Nordic level. and a second Network meeting in February 2017. progressed at NCMM over the last year? NCMM PIs reported around 50 NCMM-affi liated publica- NCMM has also added to its research expertise and talent tions in 2016, and the fi rst quarter of 2017. This includes base, by appointing three new Group Leaders, Anthony papers published in Nature Genetics, Oncogene, Current Mathelier, Nikolina Sekulic, and Irep Gözen. I greatly Biology, Journal of Clinical Oncology and many more. look forward to seeing these three new groups grow and Furthermore, there are around 27 clinical trial projects develop over the coming years. either ongoing or underway, showing that the breadth Professor Kjetil Taskén, NCMM Director and depth of research at our centre is continuing to Furthermore, NCMM has appointed an Assistant Director, develop and expand.

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5 NCMM HISTORY IN BRIEF NCMM history in brief Inaugural NCMM Network Meeting in Oslo

Second Group, Mills, rotates out

1 Group Leader 1 Group Leader hired: 3 Group Leaders hired: hired: Hurtado First Group, Mathelier Nagelhus, Mills and Morth Nagelhus, rotates out 5 new Associate Hartmut Luecke Appointment Investigators and 7 2 new Group Leaders, appointed Appointment of of 5 Associate 1 Group Leader 4th NMMN New Group Leader new Young Associate Gözen and Sekulic, Assistant Director 7 Associate Investigators EU-OPENSCREEN Investigators hired: Staerk Meeting in Oslo Esguerra hired to BiO Investigators appointed hired to BiO (2017-2021)

Taskén appointed Interim Director Taskén appointed Taskén re-appointed Director EATRIS (2009-2010) Director (2011-2015) (2016-2020)

2001-2004 2005-2007 2008 2009 2010* 2011 2012* 2013* 2014* 2015* 2016* 2017

Planning & Financing discussions Nordic EMBL Recruitment of first Official SAB 1st SAB visit 2nd SAB visit 3rd SAB visit 4th SAB visit 5th SAB visit Rotation of SAB Approval process & negotiations Partnership Agreement group leaders inauguration established Chair out, new SAB member appointed

NCMM formally Start of 1st operational First NCMM Renewal & Expansion of the Nordic EMBL Partnership Agreement (2013-2023) established operations year publications * PhD course in molecular medicine NCMM 5-year Funding for 2nd period NCMM Board re- Merger decision Merger between NCMM Board Evaluation (2015-19) secured appointed NCMM and BiO BiO and NCMM appointed BiO completed, taking total • BiO was established in 1989 number of research • After evaluation by UiO in 2002, BiO was reorganised under SAB re-appointment NCMM organised under Norway becomes groups to 11 the EMBL model UiO Faculty of Medicine official member • In 2003, Kjetil Taskén was appointed as a new Centre Director of EATRIS-ERIC, • Following the reorganisation, BiO was set up as a centre for Funding of NOR- molecular biology, biotechnology and bioinformatics OPENSCREEN as • The centre had six internationally-recruited research groups, national Norwegian in addition to core facilities. infrastructure

MERGER BETWEEN NCMM AND BIO WELCOME TO NEW NCMM ASSISTANT The merger between Centre for Molecular Medicine Following letters from the European Molecular Biology DIRECTOR, HARTMUT LUECKE Norway (NCMM) and the Biotechnology Centre of Oslo Laboratory (EMBL), The South-Eastern Norway Regional NCMM is delighted to welcome Professor Hartmut proteins, RNA editing, p53, drug discovery, and chemi- (BiO) formally came into effect on 2 January 2017. Health Authority (Helse Sør-Øst), and the Research Luecke as the Centre’s new Assistant Director. cal biology. He will therefore be an excellent addition to The new NCMM consists of two departments: NCMM Council of Norway supporting a merger, the Board of the structural biology community in Oslo. Translational Research (the former NCMM) and NCMM the Faculty of Medicine, on behalf of University of Oslo, Professor Luecke is a structural biologist currently Biotechnology (former BiO). The centre now comprises decided in June 2016 that BiO and NCMM would merge. based at the University of California, Irvine, where he is Professor Luecke studied for his B.S. at Heidelberg of 11 Research Groups. Director of the Centre for Biomembrane Systems and a University in Tiffin, Ohio, before obtaining his Ph.D. at The merger of BiO and NCMM will serve to significantly Professor of Biochemistry. Rice University in Houston, Texas. Prior to the merger, NCMM and BiO were parallel strengthen the Centre scientifically and strategically, Centres with a shared model. Both recruited young alongside reinforcing local anchoring, funding base, Professor Luecke’s research interests include crystal- Professor Luecke is expected to start working with group leaders to 5+4 year non-tenured positions, and and infrastructure. The Centre is still located at Oslo lographic and cryo-EM studies of membrane proteins, NCMM in November 2017, with a full presence at the operated with a joint Director. Science Park. with work spanning from discovering how Helicobacter centre from January 2018. pylori survives at pH 1 in the stomach, to annexins, S100

6 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 7 RESEARCH GROUPS NCMM GROUP LEADERS

From left: Anthony Mathelier, Sandra Lopez-Aviles, Nikolina Sekulic, Camila Vincencio Esguerra, Kjetil Taskén, Irep Gözen, Judith Staerk, Jens Preben Morth, Hartmut Luecke, Toni Hurtado

NCMM Biotechnology Dr. Sandra Lopez-Aviles did her PhD in Barcelona followed by a postdoc in the laboratory of Frank Uhlman at the London Research Institute. She started as Group Leader at BiO in November 2011. Her research is focussed on the role of phosphatases in the yeast cell cycle. Her appointment as group leader was evaluated in autumn 2016 and her position was renewed for a second fi ve- year period (2017-2022).

Dr. Camila V. Esguerra did her PhD at the University NCMM Group Leaders of Leuven, Belgium and was recruited to BiO from the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, where she worked as a senior scientist. Her research is in the area of chemical neuroscience using zebrafi sh as a model system for epilepsy. Esguerra started as Group Leader at BiO in December 2014. Group Leaders at NCMM should be young, outstanding researchers in an international context. Each has been recruited to non-tenured 5+4 year positions, a Group Leader at NCMM in 2011 and his research is Dr. Nikolina Sekulic did her PhD at the University of focused on breast cancer, estrogen sensitivity, and the Illinois in Chicago, followed by a postdoc in the lab- with a start-up package to set up a research group. These positions are research role of co-factors in transcriptional networks. oratory of Professor Ben Black at the University of scientist positions at a level comparable with Associate or Full Professor. Pennsylvania, Philadelphia. She started as Group Leader Dr. Judith Staerk trained at the Ludwig Institute for at BiO in January 2016 and her research is focussed on Cancer Research and Catholic University in Brussels, structural biology and epigenetics. THE CURRENT GROUP LEADERS cancer biomarkers and therapeutic targets. Mills accepted did her postdoc at Whitehead Institute, MIT, Boston, AT NCMM/BIO INCLUDE: a position at Queens University of Belfast in 2015 and US working with stem cells and started in her NCMM Dr. Irep Gözen did her PhD in chemical and biological rotated out of NCMM in June 2016. Group Leader appointment in 2012. Her research is engineering at Chalmers University of Technology in NCMM Translational Medicine focused on stem cell biology, hematopoietic stem cells Gothenburg, Sweden followed by a postdoc at Harvard- Professor Kjetil Taskén, identifi ed by the Research Council Dr. Jens Preben Morth was trained in structural biology and myelodysplastic and myeloproliferative syndromes. MIT Health Sciences and Technology. She started her as one the founding members of NCMM, served as Interim at the EMBL Outstation in Hamburg and was recruited Staerk’s appointment as group leader was evaluated in group leader appointment at BiO in September 2016 and Director 2008-10. Professor Taskén was appointed Director from Aarhus University to NCMM in October 2010. His the autumn of 2016 and her position was renewed for a her research programme will focus on the development from January 2011 and reappointed for a second 5-year research is in the area of structure and function of mem- second fi ve-year period (2017-2022). and utilization of bionanotechnology-based methods. period from 2016. His research is in the area of cell signal- brane transporters. Morth has also started a new pro- ling and immunomodulation, with application in immune gramme on pH regulation and structure function studies Dr. Anthony Mathelier is a computer scientist by back- NCMM has recently also recruited a new senior group diseases, infl ammation, and tumour immunology. on bicarbonate transporters. His research has relevance ground who did his PhD at the Pierre and Marie Curie leader/assistant director. Professor Hartmut Luecke is a to cardiology, neurobiology, and kidney diseases. Morth’s University, Paris. Mathelier was recruited from the structural biologist, currently based at the University of Dr. Ian G. Mills was recruited from Cambridge Research appointment as group leader was evaluated in 2015 and University of British Columbia, Vancouver, Canada, California (UC), Irvine and will join NCMM in November Institute, Cancer Research UK, University of Cambridge in his position was renewed for a second fi ve-year period which is where he also did his postdoc. Mathelier 2017. 2010. Mills is interested in transcriptional and regulatory (2015-2020). started his NCMM Group Leader appointment in May networks in prostate cancer and aims to better defi ne the 2016. His computational biology research programme Furthermore, NCMM will start the process of recruiting interplay between membrane traffi cking, metabolism, Dr. Toni Hurtado did his PhD at the Vall Hebron Hospital focuses on gene expression regulation and the mecha- two new group leaders in autumn 2017. The research and transcription in prostate cancer, as proteins in reg- in Barcelona and his postdoc at Cambridge Research nisms by which it can be disrupted in human diseases groups at NCMM are presented in more detail in the fol- ulatory hubs for these processes have potential value as Institute, University of Cambridge. Hurtado started as such as cancer. lowing pages.

8 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 9 RESEARCH GROUPS

Kjetil Taskén

Signalling Networks in Health and Disease

A main focus of the Taskén Group is to understand why molecular compounds) and provides “proof-of-principle” the immune system sometimes turns off its ability to rec- experiments using specific disease models. ognise and kill cells in an expanding malignant tumour. We aim to understand how tumours develop immune The Taskén group employs a breadth of techniques in evasion strategies, what mechanisms operate in differ- bioinformatics, proteomics, phospho-flow analysis, ent cancers, and how we can perturb such immune-in- chemical biology high-throughput screening assays and hibitory signals to boost anti-tumour immunity and genetic tools in order to screen new targets for in vitro assist other cancer immunotherapies. and in vivo function. In order to isolate signalling complexes from a variety of targets, including T cells, cardio- We are starting work with cancer drug sensitivity myocytes, adipocytes, and organelles such as lipid drop- screening on patient samples, looking for efficacious lets and mitochondria, a chemical genomics approach compounds and drug synergies on an individual basis, is used in combination with phospho-proteomics to ultimately aiming to assist clinical decisions in preci- understand spatiotemporal dynamics of phosphoryla- sion oncology and haematology. Other activities focus tion in anchored signalling complexes. Chemical biology on the role of the cAMP second messenger system screenings identify small molecular compounds for our and other signal networks in the regulation of cellular research. Furthermore, phospho-flow cytometry using function and its involvement in disease mechanisms fluorescent cell barcoding allows mapping of complex in inflammation as well as in infectious, metabolic and signal networks, assessing how inhibitory signals feed cardiovascular diseases. in and examining how small molecules perturb such signal networks. Our recent technology developments now also allow flow-based signalling analyses of adherent DESCRIPTION OF THE GROUP’S RESEARCH cells and high-throughput chemical biology screening by flow cytometry. The group aims to understand complex intracellular signalling networks and how such networks require The group studies cAMP immunomodulation and anchoring and localisation through A kinase anchoring involvement of regulatory T cells in HIV, mouse AIDS, proteins (AKAPs) or other scaffold proteins. The group and various cancers where tumour immunology is of investigates how these signalling networks mediate hor- significance. Projects include studies of regulatory T cells monally regulated physiological and pathophysiological and anti-tumour immune responses in colorectal cancer, processes. In the immune system we investigate cAMP- pancreatic cancer, cholangiocarcinoma and ovarian and regulatory T cell-mediated immune-modulation carcinoma. In addition, cancer and immune cell sig- with application in immune diseases, inflammation and nalling analyses are being performed by phospho-flow tumour immunology. In pursuit of this understanding the cytometry to find bio signatures. A recent interest is group maps signalling pathways, identifies targets, devel- now to rig drug sensitivity screens to explore the pos- ops tools to perturb signalling (peptidomimetics, small sibility to assist treatment choices in individualised

CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 11 RESEARCH GROUPS: KJETIL TASKÉN RESEARCH GROUPS: KJETIL TASKÉN cancer therapy, particularly looking at haematological • Won a Helse Sør-Øst (Regional Health Authority malignancies. Furthermore, systems biology analyses for South-Eastern Norway) programme grant for are applied on the phospho-flow data from single cell 2017-2019 (4.5m NOK) signalling as well as from mixed cell populations with • Co-PI on a Cancer Society programme grant to fund Treg immunosuppression. our clinical trial on ASA intervention in colorectal cancer (6m NOK) 2017-2020 The improved understanding of signalling networks can • Co-PI on a KLINBEFORSK (Department of Health and be applied to many disease states, including immune-de- Social Services) grant to fund Group’s clinical trial ficiencies, inflammatory disorders and cancers and may on ASA intervention in colorectal cancer (19m NOK) promote the development of highly specific pharmaceu- 2017-2021 ticals that maximise their therapeutic value, while mini- • Awarded UiO Innovation grant for 2017-2018 mising unwanted side-effects. (800k NOK) GROUP MEMBERS COLLABORATIONS PhD defences from the Taskén Group in 2016: ACHIEVEMENTS IN 2016 • Simer J. Bains Research Scientists International collaborations • Stalin Chelappa Einar Martin Aandahl We currently collaborate with the groups of • Professor Kjetil Taskén awarded the King Olav V’s • Nora V. Lieske Johannes Landskron Professor John D. Scott, University of Washington, Prize for Cancer Research 2016, for his work with • Alexandra Dukic Sigrid Skånland Seattle; Professor Friedrich Herberg, Universität Kassel; immunotherapy. Professor Sven Enerbäck, Göteborgs Universitet; • Paper in Journal of Clinical Oncology by Simer Bains et Some 20+ talks were held nationally Postdoctoral Fellows Professor Manuela Zaccolo, University of Oxford; al attracted significant media attention, with over 100 and internationally including: Theresa Ahrens (joint with Staerk group) Dr. Enno Klussmann, Max Delbrück Centre for press items generated. • Research Council of Norway, Industry Day, April 19, Simer Jit Bains (NCMM, affiliate) Molecular Medicine, Berlin; Professor Riitta Lahesmaa, 2016 in Det Norske Teatret. Speaker: Gene technology Deepak Balaji Thimiri Govinda Raj University of Turku; Professor Albert Heck, The Key Publications from the Taskén Group: moves boundaries in medicine. Ana I. Costa Calejo Netherlands Proteomics Centre, Utrecht; Dr. Joe Lewis, 20+ papers were published in 2016/Q1 2017, including • 43rd Scandinavian Society for Immunology meeting, Stalin Chelappa (from July 2016) Chemical Biology Unit, EMBL; Group leader Klaus co-authored papers in Cell Reports and Leukaemia, both Turku, Finland, 2016 Dinh-Toi Chu Okkenhaug, Babraham Institute, Cambridge, UK; Dr. with an impact factor of around 10. Other highlights • 19th Annual Broegelmann Lecture, Andrea Cremaschi (from October 2016) Guillaume Pidoux, Université Paris Süd; Professor include the Group’s first paper on the CLL / cancer drug University of Bergen, 2016 Aleksandra Dukic (from January 2017) Bodo Grimbacher, Freiburg University; Dr. Julio Saez- sensitivity screening (Parente-Ribes, Skånland et al) and • Int. Congress of Immunology, Melbourne, Kushi Kushekhar Rodrigues, EMBL-EBI, Hinxton / Univ of Aachen, UK; a paper in the Journal of Leukocyte Biology (Chelappa et Australia, 2016 Anna-Mari Lone Professor Mikael Elofsson, MIMS, Umeå, Sweden, Dr. al) where the journal wrote an Editorial on our paper: • Fifth International Meeting on Anchored cAMP-signal- Kristina B. Lorvik Krister Wennerberg, FIMM, Helsinki, Finland, Professor ling pathways, Zermatt, Switzerland, 2016 Vanessa L Wehbi (until January 2017) Tobias Bopp, University of Mainz and others. Parente-Ribes, A.*, Skånland, S.S.*, Bürgler, S.*, Os, • Norwegian Society for Oncology Annual Meeting, Nn, open postdoc A, Wang, D., Bogen, B., Tjønnfjord, G.E., Taskén, K.$,#, Trondheim, 2016 (Cancer Society grant, 2017- hiring ongoing) National collaborations Munthe, L.A. $,# (2016) • Oslo Life Science Conference 2017, February 6, speaker. Nn, open postdoc The group collaborates with Group Leaders Judith Spleen tyrosine kinase inhibitors block CD40L induced • Kobe University Symposium, Kobe Japan, March 14, (Helse Sør-Øst grant, 2017- hiring ongoing) Staerk, J. Preben, Morth and Camila Esguerra proliferation of chronic lymphocytic leukaemia cells. 2017. Invited Speaker. (This was tri-university collab- Nn, open postdoc Biotechnology Centre / NCMM and Professors Heidi Kiil Haematologica, 101:e59-62. oration meeting – We have signed a MOU with Kobe (KG Jebsen Centre grant, 2017- hiring ongoing) Blomhoff, Philippe Collas, Jo Klaveness, Arnoldo Frigessi, and U Washington in Seattle). Bernd Thiede, University of Oslo; Professors Dag Kvale Chelappa, S., Lieske, N.V., Hagness, M., Line, P.D., Taskén, PhD. Fellows and Anne Ma Dyrhol-Riise, Dept. of Infectious Diseases, K.,#Aandahl, E.M.# (2016) Stalin Chelappa (until June 2016) Senior Consultants Bjørn Atle Bjørnbeth and Sheraz Human regulatory T cells control TCR signalling and sus- FUNDING Aleksandra Dukic (until December 2016) Yaqub, Gastrosurgical Dept., Professor Ivar Sjaastad, ceptibility to suppression in CD4+ T cells. Nora V. Lieske (until June 2016) Institute of Experimental Medical Research, Professor J. Leukocyte Biol., 100:5-16. (#corresponding authors) In addition to support from NCMM and the Biotechnology Ellen Østensen Guttorm Haraldsen, Dept. of Pathology, Professor - In section “Spotlight on Leading Edge Research”, Centre of Oslo, the Taskén Group has, in 2016, received Ludvig Munthe, Institute of Immunology, Professor Geir Editorial: Jeschke & Williams. Treg potency and the support from: MSc/MD Students E. Tjønnfjord, Senior Consultants Ingunn Dybedahl and importance of being fit. Ibid, 1-3. Johanne Hermansen Uthus Fredrik Schjesvold, Dept. of Haematology, Professor Pål • University of Oslo – Digital Life funding Marthe Jøntvedt Jørgensen Aukrust Dr. Arne Yndestad, Professor Bente Halvorsen Professor Kjetil Taskén was senior author on a report • The Research Council of Norway and Professor Tom Hemming Karlsen; Inst. of Internal examining digital technology and its potential for – including Biotek2021, NOR-OPENSCREEN Administrative Officer Medicine Research, Professors Johanna Olweus and facilitating faster research and development, and gen- • The Norwegian Cancer Society Berit Barkley Kalle Malmberg, Dept of Immunology, Inst. for Cancer erating value within Norway’s biology economy. The • Helse Sør-Øst Res., Senior Consultant Jon Amund Kyte, Dept. of report, Digital Biology in Norway – Opportunities for • Norwegian Department of Health and Social Services Scientific Officers Oncology, and Professor Annetine Staff, Dept Ob-Gyn, Creating Value, Skills Needs, and Challenges in Economic • European Commission Marianne Enger Sen. Consultants Are Holm and Karl Otto Larsen, Dept Development, was published by Centre Digital Life – including EATRIS, EU-Openscreen Martine Schrøder of Lung Diseases, Oslo University Hospital; Professor Norway in March 2017. • Novo Nordisk Foundation Gladys Tjørhom James B. Lorens, University of Bergen, Professor Bjørn • Jebsen Centre for Cancer Immunotherapy Tore Gjertsen, Senior Consultant Line Bjørge, Haukeland Summary of grants awarded 2016/Q1 2017: • Jebsen Inflammation Research Centre University Hospital, Bergen; Professor Anders Sundan, • Awarded a Cancer Society programme grant for NTNU, Senior Researcher Geir Klinkenberg, SINTEF, 2017-2020 for the Taskén Group (6m NOK) Rafi Ahmad, Hedemark Univ. College and others.

*,$ equal contributions, #corresponding authors

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Ian G. Mills

Prostate Cancer Research Group

Prostate cancer is a high-incidence cancer in men with that regions of open chromatin are hotspots for prostate progression to metastatic disease occurring in around cancer risk loci. 20-30% of detected cases. Major translational challenges include the development of biomarkers able to pre- Autophagy: dict progression at the time of diagnosis and treatment Autophagy (‘self-eating’) is a key stress response that can response/failure as well the need to develop more effec- have pro-survival or pro-apoptotic properties in cancer tive treatment strategies. Our strategy for addressing cells depending on the context and trigger. Whilst this this has been to explore how transcription factors and has been recognised by groups worldwide, the desire to chromatin change in transformed cells and how the gene achieve clinical translational endpoints through the study networks that they regulate map back to clinical expres- of autophagy has led to the over-interpretation of assays sion profi les. From the resultant gene networks and path- and autophagic markers. A key contribution that we are way enrichments we have identifi ed biological processes making in this area is to carefully dissect whether auto- that we believe are important to regulate progression phagic markers are also necessary to drive the functional and treatment response and have gone on to study these biology of the autophagic process. We are addressing functionally and, with clinical collaborators, to evaluate this by developing and qualifying autophagic assays and candidate biomarkers. From this work the main biolog- then testing the impact of genetic targeting of autophagic ical focus of the group is on stress response signalling, factors. With that knowledge in place the programme sub-divided broadly into glycosylation and the unfolded will then move on to explore how these factors affect protein response/autophagy. In particular, we are focus- response to treatments such as anti-androgens. sing on how genes that function in these processes confer resistance to therapeutic and oncogenic stress and how Glycosylation: they can be targeted therapeutically. Glycosylation is a bridge between metabolic changes, protein folding capacity and in turn the stability and activity of oncogenes. We realised the potential importance of DESCRIPTION OF THE GROUP’S RESEARCH glycosylation early in the development of our research program based on clinical profi ling and mapping of tar- Chromatin biology and transcriptional regulation: get genes for the androgen receptor and other transcrip- Predominantly we employ high-throughput sequencing tion factors. In particular, we have been exploring how and transcript profi ling to map genome-wide changes a pathway called the hexosamine biosynthesis pathway in transcription factor recruitment and chromatin com- affects the stability of c-Myc and other oncogenes and the paction in cell-lines and clinical samples. By using these response to activators of the unfolded protein response. approaches we have found that chromatin opening is a This pathway is fuelled by metabolites drawn from all of hallmark of lethal castrate-resistant disease and that the the core metabolic processes in the cell to form a single activity of a key transcription factor in prostate cancer, amino-sugar-nucleotide conjugate – UDP-GlcNAc. Whilst the androgen receptor (AR), is modifi ed by the expres- heightened activity of this pathway is required to sustain sion of other oncogenic transcription factors with a focus protein folding in untransformed secretory cells, the here principally on c-Myc. Additionally, we have found same pathway can also confer resistance to environmen-

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tal stress and consequently the expression and activity of FUNDING COLLABORATIONS Paul Rennie/Ladan Fazli, enzymes in the pathway and fuelled by the pathway are Prostate Cancer Centre, Vancouver, Canada retained and amplified in cancer cells. In addition to support from NCMM, the Mills Group has, Thorsten Schlomm, Eppendorff Hospital, Hamburg, (Signalling and biomarkers in prostate cancer) in 2016, received additional support from: Germany (Biomarkers) Matthias Wilmanns, EMBL Hamburg, Germany Biomarkers: Henrik Gronberg/Fredrik Wiklund, (Calcium/calmodulin-dependent kinases in cancer) Since prostate cancer progresses in a subset of diagnosed • The Research Council of Norway – Young Talent Award Karolinska Institute, Sweden (Biomarkers) Tapio Visakorpi, University of Tampere, Finland cases to a lethal metastatic disease and the current bio- to Nikolai Engedal, and FIRMEDBIO David Neal, Cambridge University, UK (Biomarkers) (Chromatin biology and androgen receptor signalling marker, prostate specific-antigen (PSA), is relatively ubiq- • Helse Sør-Øst – three-year postdoc position for Dr. Kristin A. Taskén, OUS/UiO (Biomarkers) in prostate cancer/biomarkers) uitous, there is a significant need for biomarkers that flag Alfonso Urbanucci Ole Andreassen, OUS/UiO (Genetic risk) Andrei Chabes, MiMS/University of Umeå, Sweden heightened risk of disease progression. We are evaluating • Movember/Cancer Society Team Science Award Fahri Saatcioglu, OUS/UiO (Stress response signalling) (Nucleotide biosynthesis) transcripts and proteins as candidate biomarkers, focus- • The Norwegian Cancer Society – Funding for three Preben Morth, NCMM Yvonne Ceder, Lund University, Sweden sing predominantly on ‘liquid biopsy’ (urine, blood and years, for two postdocs (Calcium/calmodulin-dependent kinases in cancer) (Non-coding RNA in prostate cancer) circulating tumour cells). Amongst these sample types Judith Staerk, NCMM Anne Simonsen, UiO (Autophagy) we have so far made most progress in evaluating mark- GROUP MEMBERS (Epigenetics in haematological malignancies) Maria Theresa Landi, National Cancer Institute, ers in blood samples. Since it typically takes 5-10 years Toni Hurtado, NCMM (Transcriptional regulation Maryland, USA (Genetic risk – lung cancer) from diagnosis to disease progression, blood samples Head Engineers in hormone-dependent cancers) Olli Kallioniemi/Paivi Ostling, SciLife Lab/Karolinska represent a sample type that currently has the longest Ingrid Jenny Guldvik (until June 2016) Ole Petter Rekvig, University of Tromsø, Norway Institute, Sweden (Screening to identify sensitisers follow-up time having been biobanked. By contrast, urine Frank Sætre (until July 2016) (Lupus markers and biology in cancer) to anti-androgens) sample collections are still relatively recent and there Wolfgang Lilleby, OUS (Biomarkers) Poul Nissen, DANDRITE/Aarhus University, Denmark remains controversy over the best detection platform for Senior Researcher Suzanne Walker, Harvard University, Massachusetts, (SERCA inhibition and autophagy) circulating tumour cells. The biomarkers that we have Nikolai H. Engedal USA (OGlcNAc Transferase) Lorena Arranz, University of Tromsø, Norway been testing have arisen from three sources. Transcript Angelo DeMarzo, John Hopkins University, (Transcriptional regulation in haematological biomarkers have either been derived from our pre-clin- Guest Researcher Maryland, USA (c-Myc) malignancies) ical studies or through collaboration with international Per O. Seglen research consortia. Protein biomarkers have arisen from proteomic profiling of Janus Serum Bank samples and Postdoctoral Fellows downstream validation in samples obtained from other Harri Itkonen Nordic and UK sample collections through collaboration. Alfonso Urbanucci

PhD Fellows ACHIEVEMENTS IN 2016/Q1 2017 Lisa Gerner (until February 2017) Morten Luhr • Professor Per Seglen (Guest Researcher) Bertrand Simon – Joint PhD student at EMBL Hamburg – will be awarded the King Olav V’s Prize for Cancer (until March 2017) Research 2017 in June, in recognition of his seminal Paula Szalai work on autophagy • Lisa Gerner (PhD student) – successfully defended her thesis in Q1 2017 • Bertrand Simon (PhD student – co-supervised by Ian Mills but based at EMBL Hamburg) – successfully defended his thesis in Q1 2017

Publications from Mills Group 2016/Q1 2017 Some 20+ publications were published in 2016/Q1 2017, including co-authored papers in high impact factor jour- nals, such as Nature Genetics, Journal of the National Cancer Institute, European Urology, Autophagy, and many more.

16 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 17 RESEARCH GROUPS

J. Preben Morth

Membrane Transport Group

The Morth group employs a structural systems biology P-type ATPases in infectious diseases approach to investigate the proteins involved in acid- The system is strongly dependent on the ion gradients base homeostasis and metal ion transport across the maintained by the P-type ATPases. The group therefore cellular membrane. A variety of techniques are used aims to develop a complete structural model for anion in order to identify and characterise both soluble and transport and recognition. Structural analysis of P-type membrane bound proteins involved in pH regulation. ATPases will continue with focus on the prokaryotic A bioinformatics approach is used to target new pro- Ca2+ ATPases and Mg2+ ATPases. In particular, we teins and interaction partners of interest. Furthermore, are focusing on their function as participants in viru- X-ray crystallography and several biophysical methods lence systems. The systems in question originate from to obtain structural information as well as biochemical Listeria monocytogenes and Salmonella typhimurium, techniques are also used, including activity assays and and our work on translation in infectious diseases like fluorescence spectroscopic measurements. Salmonella will bridge the gap between lab bench and clinic. Our strong focus on developing in vitro assays to study these particular membrane transporters will DESCRIPTION OF THE GROUP’S RESEARCH allow direct inclusion into the exciting drug screening platforms in Europe. Furthermore, these projects can To study the 3D atomic structure of membrane proteins, benefit the broad scientific community located in Oslo, the group is currently developing purification and lipid focusing on infectious diseases. vesicle reconstitution protocols. The aim is to purify and characterise these membrane proteins. Characterisation of supramolecular Tankyrase complexes implicated in colorectal cancer, using an The bicarbonate transporters intrinsically disordered protein as bait. Acid-base homeostasis is fundamental to our under- A translational project focusing on identification of standing of human physiology and is essential to cel- large supramolecular complexes implicated in the lular function. The main buffering system found in the Wnt pathway was initiated by the Morth group. We human body is based on bicarbonate. The SLC4 proteins are performing structural studies of a human ADP- are the main facilitators of bicarbonate transport across ribosyltransferase tankyrase (TNKS), trying to identify the plasma membrane, however, not much is known novel direct interaction partners by using a proteomics about the structural basis of function and regulation approach in collaboration with Bernd Thiede (UiO). of these. The N-terminal cytoplasmic domain (NTD) of Tankyrases belong to the poly (ADP-ribose) polymerase the sodium-coupled chloride bicarbonate exchanger (PARP) superfamily and are involved in various cellular (NCBE), found predominantly in the choroid plexus of functions such as telomere maintenance, centrosome the brain, has been cloned, expressed and purified. The maturation, Wnt signalling, embryonic development core domain found centrally in the NTD has been crys- and the pathogenesis of Cherubism. We are currently tallized and the structure determined at 4.0 Å resolution. aiming to isolate and characterise proteins that bind The NTD of NCBE is found to contain regions of intrinsic to the full length tankyrase enzyme, a protein of more protein disorder and these disordered regions are con- than 1200 residues and with several potential and ver- served among all bicarbonate transporters of the SLC4 ified interaction partners. We are therefore combining family. The disordered regions coincide with regions of our structural and biochemical studies with cellular sequence variation, indicating that although sequence is assays, using the strong imaging platforms built up by not conserved, the disorder is. Oddmund Bakke (UiO).

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ACHIEVEMENTS IN 2016 FUNDING

Publications from the group: In addition to support from NCMM, Morth Group has, Bauer J, Bakke O, Morth JP. Overview of the mem- in 2016, received additional support from: brane-associated RING-CH (MARCH) E3 ligase family. N Biotechnol. 2016 Dec 14. pii: S1871-6784(16)32629-2. • The Norwegian Cancer Society doi: 10.1016/j.nbt.2016.12.002. [Epub ahead of print] • The Research Council of Norway PubMed PMID: 27988304. • Marie Curie • NordForsk Gerner L, Munack S, Temmerman K, Lawrence-Dörner AM, Besir H, Wilmanns M, Jensen JK, Thiede B, Mills IG, Morth JP. Data for the co-expression and purifi ca- GROUP MEMBERS tion of human recombinant CaMKK2 in complex with calmodulin in Escherichia coli. Data Brief. 2016 Jun 29; Principal Engineer 8:733-40. doi:10.1016/j.dib.2016.06.033. eCollection 2016 Bojana Sredic Sep. PubMed PMID: 27508226; PubMed Central PMCID: PMC4950174. Postdoctoral Fellows Johannes Bauer Bjerregaard-Andersen K, Østensen E, Scott JD, Taskén K, Harmonie Perdreau-Dahl Morth JP. Malonate in the nucleotide-binding site traps Saranya Subramani human AKAP18γ/γ in a novel conformational state. Acta Crystallogr F Struct Biol Commun. 2016 Aug; 72(Pt PhD Fellow 8):591-7. doi:10.1107/S2053230X16010189. Epub 2016 Jul Julia Weikum (from April 2017) 13. PubMed PMID: 27487922; PubMed Central PMCID: PMC4973299. Students Annika Kratzel, Erasmus Student (April - July 2017) Leo JC, Oberhettinger P, Yoshimoto S, Udatha DB, Morth Maria Wahle (May - September 2017) JP, Schütz M, Hori K, Linke D. Secretion of the Intimin Passenger Domain Is Driven by Protein Folding. COLLABORATIONS J Biol Chem. 2016 Sep 16; 291(38):20096-112. doi: 10.1074/ jbc.M116.731497. Epub 2016 Jul 27. PubMed PMID: Oddmund Bakke, Department of Biosciences, UiO 27466361; PubMed Central PMCID: PMC5025694. Sandip Kanse, Institute of Basic Medical Sciences, UiO Maria Eugenia Chollet Dugarte, Oslo University Hospital Hong Z, De Meulemeester L, Jacobi A, Pedersen JS, Morth Grethe Skretting, Oslo University Hospital JP, Andreasen PA, Jensen JK. Maria Skepo, Lund University, Sweden Crystal Structure of a Two-domain Fragment of Lise Arleth, Copenhagen University, Denmark Hepatocyte Growth Factor Activator Inhibitor-1: Michael Palmgren, Copenhagen University, Denmark FUNCTIONAL INTERACTIONS BETWEEN THE KUNITZ- Kresten Lindorff-Larsen, Copenhagen University, TYPE INHIBITOR DOMAIN-1 AND THE NEIGHBORING Denmark POLYCYSTIC KIDNEY DISEASE-LIKE DOMAIN. Michele Cascella, Department of Chemistry, UiO J Biol Chem. 2016 Jul 1; 291(27):14340-55. doi: 10.1074/ William Louch, Oslo University Hospital (Ullevål) jbc.M115.707240. Epub 2016 May 6. PubMed PMID: 27189939; PubMed Central PMCID: PMC4933187.

Gerner L, Munack S, Temmerman K, Lawrence-Dörner AM, Besir H, Wilmanns M, Jensen JK, Thiede B, Mills IG, Morth JP. Using the fl uorescent properties of STO-609 as a tool to assist structure-function analyses of recombinant CaMKK2. Biochem Biophys Res Commun. 2016 Jul 22; 476(2):102-7. doi: 10.1016/j.bbrc.2016.05.045. Epub 2016 May 11. PubMed PMID: 27178209.

Subramani S, Perdreau-Dahl H, Morth JP. The magnesium transporter A is activated by cardiolipin and is highly sensitive to free magnesium in vitro. Elife. 2016 Jan 18; 5. pii: e11407. doi: 10.7554/eLife.11407. PubMed PMID: 26780187; PubMed Central PMCID: PMC4758953.

20 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 RESEARCH GROUPS

Antoni Hurtado

Breast Cancer Group

The main interest of the group is to understand the and analysing their effect on FOXA1 activity. mechanism of hormone resistance in breast cancer. Subsequently, we performed the chemical screening Moreover, we are interested in determining how the in hormone-sensitive and hormone-resistant cell lines, estrogen antagonist Tamoxifen contributes to the inhibi- which were positive for the expression of FOXA1. We tion of breast cancer progression. Therefore, the focus of identified 23 potential kinases targeting FOXA1. Next, we my future research is summarised in two main projects: repeated the drug screening with 45 inhibitors targeting (1) Elucidating the role of cell-signalling pathways con- these kinases. As a proof of principle, with this system trolling FOXA1 functions in Breast Cancer (2) Searching we could confirm our previous results regarding the reg- for novel mechanisms of action for the anti-ER drug ulation of FOXA1 by the HER2 pathway. Taken together, Tamoxifen. our preliminary results show that our reporter system is appropriate as a first approach to investigate FOXA1 function and also suggest that FOXA1 mediates the sig- DESCRIPTION OF THE GROUP’S RESEARCH nals of these kinases in the control of proliferation for hormone-resistant patients. Elucidating the role of cell-signalling pathways controlling FOXA1 functions in Breast Cancer Searching for novel mechanisms of action for the anti- ER drug Tamoxifen Resistance to endocrine therapy is complex, heterogeneous and may differ from patient to patient. The majority To date, the precise mechanism of action of Tamoxifen is of clinical trials thus far have focused on combining or not completely understood, mainly due to the fact that alternating endocrine therapy agents, or intercalating the current studies on the molecular characterisation targeted therapies against kinase inhibitors such as of tamoxifen action are based on the idea that those CDK, PI3KAKT-mTOR, EGFR or HER2. However, cancer compounds target exclusively ER (Shang, Cell 2000). cells can eventually find other means to proliferate, and However, the more we understand about the molecular therefore escape the arrest imposed by these treatments. mechanisms of other drugs targeting other proteins, the For instance, treatment with AKT inhibitors has been more we realize that they are generally promiscuous shown to induce activation of SGK1, which continues with regard to their biological targets and effects. Hitting to support cell proliferation (Castel, Cancer Cell 2016). multiple targets can enable a drug to be applied thera- Having seen that FOXA1 was an important mediator of peutically in several potentially unrelated diseases; or, if HER2/HER3 signalling (Gilfillan, Nat Communication in more than one of the drug’s targets is involved in path- resubmission), we decided to study how other pathways ways relevant to a particular disease, the drug may have with implications in cell proliferation could regulate its increased efficacy for this therapeutic application. For function. Our final goal is to better understand the mech- instance, the anti-ER drugs Tamoxifen and Fulvestrant anisms that lead to resistance to current treatments increase Bcl-2 levels and inhibit growth of breast car- and that are mediated by FOXA1. To test whether other cinoma cells by modulating PI3K/AKT, ERK and IGF-1R kinases impact FOXA1 function, we have carried out a pathways independently of ER (Long, JBC 2006). drug screening using a selected subset of kinases and phosphatases with known implications in breast cancer,

CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 23 RESEARCH GROUPS: ANTONI HURTADO

In this study, we aimed to identify targets relevant for FUNDING Tamoxifen repressive action. We used a chemical proteomics approach, which allows the identifi cation of drug In addition to support from NCMM, the Hurtado Group targets. Next, we performed proteomics to identify novel has, in 2016, received additional support from: Tamoxifen-interacting proteins and compared to protein targets of ER-tamoxifen. Importantly, this targeted pro- • The Norwegian Cancer Society teomics approach revealed that 50% of the Tamoxifen- • EU FP7-PEOPLE-2013 COFUND - Sciencia Fellow biotin pulled down proteins were also identifi ed within programme the ER-Tamoxifen pull down, which confi rmed the suit- • Research Council of Norway - Frimedbio Young ability of this method to identify Tamoxifen-interacting Talent programme proteins. • Helse Sør-Øst (HSØ) - Open Project

In addition, we have also identifi ed other proteins not present within the list of ER-interacting proteins. Tamoxifen- GROUP MEMBERS associated proteins identifi ed at least in two replicates and excluded from the negative control (biotin beads) Head Engineer were considered as positive hits. Among these Tamoxifen Siv Gilfi llan ER-independent targets we have identifi ed the protein SKIP, which is an important modulator of TGF-beta/Smad Postdoctoral Fellows signalling. Previously, it has been reported that ER and Anne Marthe Fosdahl TGFbeta signalling have opposite roles in proliferation Sachin Kumar Singh (from September 2016) and apoptosis. Whereas ER induces a transcriptional pro- Venkata Sateesh Somistetty (until January 2017) gram that triggers proliferation and inhibits apoptosis, TGF-beta induces cell growth arrest and promotes apop- PhD Fellow tosis (Band, Mammary Gland Biology Neoplasia 2011). Shixiong Wang Moreover, their regulatory pathways intersect, and ER blocks TGF-beta pathway by multiple means, including MSc Student direct interactions of its signalling components Smads Neus Daviu (Band, Mammary Gland Biology Neoplasia 2011). (Erasmus student, September 2016-April 2017)

Considering the intricate roles of these major signalling pathways in mammary epithelial cells biology and tum- COLLABORATIONS origenesis, and their extensive interactions, we are currently investigating how Tamoxifen regulates the cross- Dr. Therese Sørlie, talk between these pathways. Oslo University Hospital Prof. Camilla Krakstad, University of Bergen ACHIEVEMENTS IN 2016 and Haukeland University Hospital, Bergen, Norway Prof. Vessela Kristensen, • Paper published in Nucleic Acids Research (NAR) by Oslo University Hospital Elisa Fiorito (PMID: 27638884); Hurtado lead author Dr. Preben Morth, NCMM • The manuscript ‘Breast tumours escape endocrine Dr. Minna U. Kaikkonen, therapy by ER-independent mechanisms triggered University of Eastern Finland by the coordinated activities of HER2/3 and deacetyl- Dr. Meritxell Bellet, ated FOXA1’ by Gilfi llan et al is re-submitted to Nat Vall-Hebron Research Institute, Barcelona, Spain Communications Dr. Jason Carroll, CRI-CRUK, Cambridge, UK • The manuscript ‘DNA methylation at enhancers distin- Dr. Maurizio Scaltriti, guishes distinct breast cancer lineages’ by Fleischer et Memorial Sloan Kettering Cancer Center, NY, USA al is re-submitted to Nat Communications • The manuscript ‘FOXA1 predicts good outcome in HER2+ endometrial cancer patients by inhibiting EGFR/HER2 signalling’ by Gilfi llan et al is re-submitted to Journal of the National Cancer Institute.

24 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 RESEARCH GROUPS

Judith Staerk

Stem Cell Group

The Staerk Group focuses on deciphering molecular pro- cells, 5hmC primes expression of genes regulating mye- cesses that govern hematopoietic specification, hemato- loid and lymphoid lineage commitment. Moreover, in poietic stem cell (HSC) renewal and differentiation as CD34+ cells, 5hmC at enhancers was associated with well as formation of mature blood cells. Understanding increased binding of RUNX1 and FLI1 that are TFs cru- the mechanisms governing blood development is needed cial for haematopoiesis. To further investigate the role to decipher the underlying molecular events that drive of 5hmC during human blood cell differentiation, the lifelong formation of blood cells, and to identify path- group established oxBS-seq and deleted endogenous ways that are dysregulated in blood disorders. TET2 and/or TET3 in hESC lines that encode reporter genes to monitor blood cell differentiation. The overall goals of the group’s research are to: i) functionally characterise epigenetic and genetic factors and Projects with translational impact signalling pathways during hematopoietic development, Myelodysplastic syndromes (MDS) are a heterogeneous ii) decipher the mechanism by which the nuclear lamina group of clonal hematopoietic disorders characterised by modulates hematopoietic development, and iii) identify impaired haematopoiesis and a predisposition to devel- underlying molecular causes of myeloid blood disorders oping acute myeloid leukaemia (AML). The underlying triggered by defects in lineage differentiation that the cause for MDS is incompletely understood. The group group studies in the physiologic setting. To achieve these is using primary patient samples as well as patient-de- goals, the group is using human pluripotent stem cells, rived induced pluripotent stem cells to analyse the in vitro differentiation assays, as well as animal models potential of these iPSC to differentiate into hematopoi- along with primary patient samples. The group combines etic progenitors, and to screen transcription factor and these assays with genetic and genomic approaches. miRNA libraries to identify candidate genes to reverse the potential block in in vitro blood cell differentiation.

DESCRIPTION OF THE GROUP’S RESEARCH Chronic lymphocytic leukemia (CLL) is a common hema- tological cancer in adults and is characterised by clonal Epigenetic dynamics during blood cell differentiation B cell expansion. In the past year, the group assessed cell One focus of the group is to understand how epige- cycle defects in CLL, and found that a significant num- netic signatures influence cell fate determination dur- ber of CD19+ B cells isolated from peripheral blood CLL ing mesoderm and hematopoietic cell specification. samples are arrested in cytokinesis. The group linked DNA methylation is an epigenetic modification, which the observed cytokinesis arrest to reduced NuMA and is key to numerous processes, including regulation of p53 protein levels, and showed that proteins known to gene expression and maintaining genomic integrity. be crucial for cell division, checkpoint and centromere Additional complexity to the overall gene regula- function were dysregulated. tion has been added by the discovery of Ten-Eleven- Translocation (TET) enzymes, which are dioxygenases Lamin proteins and haematopoiesis that catalyse the conversion of 5-methylcytosine (5mC) More recently, the Staerk group has developed an inter- to 5-hydroxymethylcytosine (5hmC). The group char- est in the nuclear lamina (NL)/lamin proteins. Lamins are acterised 5hmC distribution in CD34+ cells, and mature divided into A-type lamins that are expressed in most blood lineage cells. Our results showed that in CD34+ somatic cell types, but are not expressed in stem cells,

CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 27 RESEARCH GROUPS: JUDITH STAERK PHOTO: JO MICHAEL

while B-type lamins (LMNB1 and LMNB2) are highly GROUP MEMBERS expressed in both, stem cells and differentiated cell types. Apart from the well-established role in forming Principal Engineer a scaffold underneath the inner nuclear membrane, the Kirsti E. Præsteng NL has been implicated in nuclear positioning of chromatin and transcriptional regulation, which is thought Postdoctoral Fellows to be critical for cell fate decisions. Moreover, recent Theresa Ahrens studies show that a mutation in lamin A/C (LMNA) leads Safak Caglayan to altered distribution of histone H3 lysine 27 trimethyla- Artur Cieslar-Pobuda tion (H3K27me3) in fi broblasts, implicating the interplay Adnan Hashim between the NL, the epigenetic landscape and probably Marie Rogne also direct interaction with epigenetic enzymes. When the process of characterising changes of NL components PhD Fellows more closely was started, the group was surprised to Julia Madsen-Østerbye fi nd very few studies addressing lamin protein function Oksana Svärd in blood cells. The group uses ChIP-Seq analysis and generated human ESC that are defi cient or overexpress components of the NL to more closely assess how lamin COLLABORATIONS proteins affect human blood development. Stefan N Constantinescu, Ludwig Institute for Cancer Research, Brussels, Belgium ACHIEVEMENTS IN 2016 Petr Bartunek, Institute of Molecular Genetics, Prague, Czech Republic Publications Karl-Johan Malmberg, OUS/UiO Tekpli X, Urbanucci A, Hashim A, Vågbø CB, Lyle R, Geir Tjønnford, OUS Kringen MK, Staff AC, Dybedal I, Mills IG, Klungland A, Ingunn Dybedal, OUS Staerk J. Changes of 5-hydroxymethylcytosine distribution during myeloid and lymphoid differentiation of CD34+ cells. 2016. Epigenetics Chromatin. May 31; 9:21.PMID: 27252783

FUNDING

In addition to support from NCMM, the Staerk Group has, in 2016, received additional support from:

• The Cancer Society • The Research Council of Norway – Stem Cell Programme and Young Talent Grant • University of Oslo • FP7-CoFund

28 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 RESEARCH GROUPS

Anthony Mathelier

Computational Biology and Gene Regulation

The Mathelier Group develops and assesses computa- mutations within TF binding sites can alter gene expres- tional methods to analyse genomic sequences (DNA). sion, triggering human diseases such as cancer. The goal of the group is to create the next generation of As successful computational biology research relies on cutting-edge algorithms and open computational biology high quality data for which the group has a strong under- software, with immediate application to real-life biologi- standing, work is currently focused on combining large cal problems. amounts of experimental data with in house computational models to identify the binding sites of TFs. This work will provide the group with a critical map of where DESCRIPTION OF THE GROUP’S RESEARCH TFs bind in the human genome for further studies.

The group’s computational biology research program The group next plans to combine whole genome sequenc- aims at furthering the understanding of gene expression ing and gene expression data from cancer patient sam- regulation (when and where genes are expressed), and ples with its high-quality regulatory map. This will the mechanisms by which it can be disrupted in human provide new insights into the predictions of the impact diseases such as cancer. of the mutations dysregulating gene expression and con- tributing to cancer. Thanks to high-throughput sequencing technologies, the group has unprecedented opportunities to study the human genome in the context of diseases. While most studies have focused on genomic regions encoding for proteins (and representing only ~2% of the human genome), the group tries to predict which mutations in cis-regulatory DNA regions (switches to regulate when and where genes are transcribed from DNA to RNA) are causal for diseases.

Transcription factors (TFs) are key proteins binding to these switches to control when, where, and to what extent genes are transcribed. It has been shown that

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ACHIEVEMENTS IN 2016 FUNDING

Lab started in May 2016; early hires include a PhD stu- Support received from NCMM dent and a Postdoctoral Fellow.

Publications GROUP MEMBERS • A. Khan and A. Mathelier. Intervene: a tool for intersection and visualization of Postdoctoral Fellow multiple gene or genomic region sets. Aziz Khan bioRxiv, 2017. https://doi.org/10.1101/109728 • C.-H. Lecellier, W.W. Wasserman, R. Rohs, and A. PhD Student Mathelier. Human enhancers associated with immune Marius Gheorghe response harbour specific sequence composition, activity, and genome organization. bioRxiv, 2016. Master Student https://doi.org/10.1101/078477 Eleftherios Pavlos (Erasmus student, Oct. 2016-Mar. 2017) • M. Lizio, J. Harshbarger, I. Abugessaisa, S. Noguchi, A. Kondo, J. Severin, C. Mungall, D. Arenillas, A. Mathelier, Y.A. Medvedeva, A. Lennartsson, F. Drabløs, COLLABORATIONS J.A. Ramilowski, O. Rackham, J. Gough, R. Andersson, A. Sandelin, H. Ienasescu, H. Ono, H. Bono, Y. Vessela Kristensen, Oslo University Hospital Hayashizaki, P. Carninci, A.R.R. Forrest, T. Kasukawa* Hege Russness, Oslo University Hospital and H. Kawaji*. Update of the FANTOM web resource: Benoît Ballester, French Institute of Health and Medical high resolution transcriptome of diverse cell types in Research, Paris, France mammals. Charles-Henri Lecellier, Institute of Molecular Genetics of Nucleic Acids Research, 2016. doi: 10.1093/nar/gkw995 Montpellier, France • A. Mathelier, B. Xin, T.-P. Chiu, L. Yang, R. Rohs, and W.W. Wasserman. DNA Shape Features Improve FANTOM consortium (JASPAR project) Transcription Factor Binding Site Predictions In Vivo. Groups of: Cell Systems, 2016. doi:10.1016/j.cels.2016.07.001 Wyeth Wasserman, University of British Columbia, • D.J. Arenillas, A. Forrest, H. Kawaji, T. Lassman, the Vancouver, Canada FANTOM consortium, W.W. Wasserman+, and A. Boris Lenhard, Imperial College London, UK Mathelier+. CAGEd-oPOSSUM: motif enrichment anal- Albin Sandelin, Copenhagen University, Denmark ysis from CAGE-derived TSSs. Bioinformatics, 2016. doi: 10.1093/bioinformatics/btw337

The group’s paper, “DNA Shape Features Improve Transcription Factor Binding Site Predictions In Vivo” has been highlighted in Cell Systems with a preview article by G.D. Stormo and B. Roy (http://www.cell.com/cell/ abstract/S2405-4712(16)30294-0).

The same paper (“DNA Shape Features Improve Transcription Factor Binding Site Predictions In Vivo”) has been featured during ECCB 2016: the 15th European Conference in Computational Biology with a highlight talk.

A series of seminars, the Sven Furberg Seminars in Bioinformatics and Statistical Genomics (http://www. mn.uio.no/ifi/english/research/networks/clsi/seminars/), for which Anthony Mathelier has received funding from UiO:Life Science, were officially launched in March 2017.

32 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 RESEARCH GROUPS Sandra Lopez-Aviles

Cell Cycle Regulations Group

The Group’s main research interest is the study of cell More specifically, we are interested in understanding: cycle regulation, in particular transitions into and out of mitosis. Classically, the focus of attention in the field Regulation of mitotic progression by protein has been on understanding the processes regulated by phosphatases, particularly type-2A phosphatases protein kinases (especially Cyclin-Dependent Kinases or We examine the role of phosphatase activity in the CDKs) and on how their activity is temporally and spa- ordering of Cdk-substrates dephosphorylation, as well tially regulated for an ordered cell cycle progression. as in the engagement of feedback loops that lead to the irreversible inactivation of Cdk complexes during mitotic In our laboratory, however, we are interested in the exit. We also investigate how phosphatase activity influ- role of the CDK opposing activity, that is, protein phos- ences the behaviour of cells during a sustained mitotic phatases. We focus our efforts in studying the processes arrest. Since cells arrested in mitosis for long periods regulated by protein phosphatases that are relevant to eventually undergo programmed cell death, understand- cell cycle progression, and that could have a repercus- ing the mechanisms that can prolong this arrest will be sion on our understanding of the cell cycle. instrumental in order to improve the efficacy of current cancer treatments.

DESCRIPTION OF THE GROUP’S RESEARCH Interplay between phosphatase activity and signalling pathways regulating cell growth and differentiation Cell cycle control is very intricate; it is modulated by We have shown that the phosphatase PP2A-B55 plays external and internal stimuli, and transitions between an important role in connecting the activities of the two the different phases are prompted by the engagement TOR complexes, TORC1 and TORC2. This becomes par- of feedback loops. Although phosphatase activity has ticularly relevant during nutritional deprivation, a sig- been assumed to participate in this control, its role has nal that in yeast leads to cellular differentiation. Given been commonly regarded as non-regulated. This per- this special relation between TOR signalling and PP2A, ception is, however, changing, and new data is accu- we are now studying the implication of PP2A activity mulating in favour of a controlled phosphatase activity in other processes regulated during nutritional stress timing the events of the cell cycle. by TOR signalling. In particular, we are addressing the involvement of PP2A in the regulation of protein transla- Nevertheless, protein phosphatases are still difficult to tion, as well as in the regulation of epigenetic marks and study due to their pleiotropic effects in the cell and, in gene transcription. this regard, the use of more simple organisms is key to understand their basic functions. With this idea in Mechanisms controlling cell cycle arrest during mind, we have developed our research using a yeast cellular differentiation model, Schizosaccharomyces pombe, and looking at In yeast as in mammals, cell differentiation can only individual phosphatase complexes during specific occur if cells have previously stalled their progression phases of the cell cycle or cellular responses. In trying through the cell cycle in G1 phase. Hence, differentiation to simplify the picture that we are studying, we can signals control the activity of key proteins involved in achieve a clearer view of the essential functions of cell division. We are trying to understand the mecha- these phosphatases and ultimately extrapolate them to nisms that lead to this control, specifically in the context more complex scenarios. of nutrient sensing. The same mechanisms should be relevant to understand how the cell regulates the length of the different cell cycle phases in response to different nutritional inputs.

CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 35 RESEARCH GROUPS PHOTO: JO MICHAEL

ACHIEVEMENTS IN 2016

Our group’s key achievement was the publication of our work in Current Biology:

Martin-Martin, R., Portantier, M., Chica-Balaguera, N., Nyquist-Andersen, M., Mata, J., Lopez-Aviles, S. A PP2A-B55-mediated crosstalk between TORC1 and TORC2 regulates the differentiation response in fi ssion yeast. (Current Biology, 2017 Jan 23; 27(2):175-188)

FUNDING

In addition to support from NCMM, the Lopez-Aviles Group has, in 2016, received additional support from:

• The Norwegian Cancer Society • EU, FP7 Scientia fellows, co-fund through FP7 Marie Curie Actions • The Research Council of Norway

GROUP MEMBERS

Engineer Mari Nyquist-Andersen

Postdoctoral Fellows Dr. Nathalia Chica-Balaguera Dr. Marina Portantier

Researcher Ruth Martîn Martîn

COLLABORATIONS

Dr. Juan Mata, University of Cambridge, UK Dr. Beata Grallert, Institute for Cancer Research, Radium Hospital, Oslo, Norway Dr. Maria Hernandez-Valladares, PROBE, University of Bergen, Norway Dr. Damien Coudreuse, Institute of Genetics and Development of Rennes, France Dr. Nikolina Sekulic, NCMM

36 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 RESEARCH GROUPS Camila Vicencio Esguerra

Chemical Neuroscience Group Dr. Esguerra´s research team is focused on exploring the fundamental mechanisms underlying brain function in health and disease.

Research focus GROUP MEMBERS Using a combination of genetic and chemical approaches in zebrafish, the group seeks to elucidate the mechanisms Head Engineer of seizure generation, epileptogenesis and treatment Rønnaug Steen Kolve resistance by probing the function of novel disease-associated gene variants involved in the etiology of phar- Postdoctoral Fellows macoresistant epilepsies. The Esguerra Group is using David Ramonet-Jimenez (from September 2016) engineered zebrafish mutants and transgenic reporter Ettore Tiraboschi lines as well as pharmacological seizure models for car- rying out in vivo chemical modifier screens to identify Research Technician novel neuropharmacological tools and drug leads. These Daniel James Wrobleski (from February 2016) models and neuroactive small molecules will serve as valuable tools towards understanding the development, MSc Students function, and diseases of the brain. Gezime Seferi (from February 2017) Anna Thao Nguyen (from August 2016 until May 2017) Aims: 1. Generate novel pharmacoresistant zebrafish epilepsy models COLLABORATIONS 2. Functionally confirm disease-causative gene variants in vivo (genotype-phenotype correlation) Prof. Holger Lerche, Hertie Institute for Neuroscience, 3. Identify bioactive small molecules with potential utility University of Tuebingen, Tuebingen, Germany as anti-epileptic drug leads and pharmacological tools Functional analysis of novel gene variants associated 4. Elucidate mechanisms of action of identified small with epileptic encephalopathies molecules Prof. Sanjay Sisodiya, University College London, London, UK ACHIEVEMENTS IN 2016 Functional analysis of novel gene variants associated with photosensitive epilepsies David Ramonet awarded the Scientia Marie Curie Prof. Andreas Turski, Medical Univ. of Lublin, Lublin, Postdoctoral Fellowship. Poland Epileptogenic mechanisms of chemoconvulsant compounds Prof. Anne Simonsen, University of Oslo FUNDING In vivo functional analysis of autophagy genes Prof. Thomas Arnesen, University of Bergen In addition to support from NCMM, the Esguerra N-Acetyltransferase (NAT) and NAT inhibitor function Group has, in 2016, received additional support from: in vivo • NFR (DigiBrain project, Zebrafish work package): Prof. Kjetil Taskén & Dr. Judith Staerk, NCMM Three year PhD student fellowship, plus running costs Zebrafish as a model for cancer drug sensitivity • EU/UiO Marie Curie Scientia Postdoctoral fellowship: screening Two year postdoctoral fellowship, plus running costs; Prof. Marianne Fyhn (Coordinator) et al., Mechanism of action of novel anticonvulsant compound University of Oslo • NFR (NOR-OpenScreen): Automated Zebrafish DigiBrain (elucidating molecular mechanisms Behavioral Tracke, Fluorescence Stereomicroscope of Schizophrenia)

CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 39 RESEARCH GROUPS

Nikolina Sekulic

Structural Biology and Chromatin Group

DESCRIPTION OF THE GROUP’S RESEARCH ACHIEVEMENTS IN 2016

The Sekulic Group uses modern biophysical methods in The Group officially started at NCMM in January 2016, combination with structural and cell biology to answer with the appointment of Nikolina Sekulic from the important questions in the field of chromatin biology. University of Pennsylvania. Group and lab established with the appointment of a senior researcher and prin- The group is particularly interested in the centromere - cipal engineer. the part of the chromosome that governs chromosome segregation during cell division. On average, one hundred Lab equipment was installed, including an INFOS billion cells divide in our body every day. Throughout shaker that can incubate up to 10L of bacterial media, this division and replication, our cells will each retain the AKTA pure system, Akta Prime system and Bio-Rad same number of chromosomes, with genes faithfully car- PrepCell system for protein purification, Agilent Carry rying our genetic code. The group’s research is helping to 60 UV-Vis spectrophotometer with 16-cells holder for build a better picture of what exactly keeps our genome enzyme kinetics and much more. safe throughout this process. Nikolina was awarded a UiO infrastructure grant to pur- Dr. Sekulic’s previous work in the lab of Professor Ben chase an instrument to measure hydrogen-deuterium Black at the University of Pennsylvania has set the foun- exchange in proteins that is monitored by mass spec- dation for biochemical understanding of centromeres by trometry (HDX-MS). providing the first high-resolution structure of specialised • This is a powerful technique that provides dynamic histone (CENP-A) that is defining these chromosome loci. information about proteins and protein complexes • This instrument is the first one of its kind in Norway, The Sekulic Group is interested in understanding what and Nikolina’s group will lead in establishing this unique properties of this histone are generating special- powerful technique in the country ised chromatin at centromeres. Furthermore, the group • The instrument will be available for use to other groups is working on building a better understanding of the role in UiO and in the rest of the country of other centromere-associated proteins and dynamics of their association with centromere during cell division. Nikolina was nominated by fellow NCMM member, Dr. The research will also help with further understanding the Preben Morth, as Norwegian representative member for basic mechanisms that underlie how genetic information eCOST action BM 1403 “Native mass spectrometry and is maintained through division and duplication as well as related methods for structural biology”. This will help the processes that lead to cancer. These findings will hope- her to build links with the European mass spectrome- fully provide possible new avenues for fighting the disease. try community, which is working on establishing and

CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 41 RESEARCH GROUPS: NIKOLINA SEKULIC

developing methods like HDX-MS. Nikolina was invited FUNDING to eCOST meeting in Greece in March 2017 where she presented her previous work involving use of HDX-MS In addition to support from NCMM, the Sekulic Group has, in 2016, received additional support from: Nikolina was awarded a 3-year Young Talent Award from the Norwegian Research Council to study the molecular • University of Oslo – Infrastructure Grant basis for genome stability. The grant focuses on struc- • The Research Council of Norway – Young Talent Award tural and biochemical studies of protein shugoshin that is responsible for holding duplicated chromosomes together through process of cell division assuring equal GROUP MEMBERS segregation in daughter cells. This money will be used to expand the group and secure the necessary resources Principal Engineer for research. Stine Malene Hansen Wøien

Key Publications from Nikolina Sekulic Postdoctoral Fellow Several publications from Nikolina’s work at University Dario Segura-Peña of Pennsylvania were published during the year, including: COLLABORATIONS Sekulic N, Black BE. Preparation of Recombinant Centromeric Nucleosomes Sandra Lopez-Aviles, NCMM and Formation of Complexes with Nonhistone Ben Black, University of Pennsylvania, USA Centromere Proteins. Benjamin Garcia, University of Pennsylvania, USA Met Enzymol. 2016 2016;573:67-96. doi: 10.1016/ bs.mie.2016.01.014.

42 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 RESEARCH GROUPS

Irep Gözen

Bionanotechnology and Membrane Systems

The Gözen Group uses soft biomaterials, such as lipid Endoplasmic reticulum dynamics membranes, to mimic the behaviour of living cells. The endoplasmic reticulum (ER) consists of a complex, three-dimensional mesh of lipidic tubular structures, in By modelling a complex cell with minimal forms in which the arrangement of tubes changes rapidly over experiments, the group aims to gain a deeper under- time. The function of ER relies on its peculiar morphol- standing of certain biological processes, including ogy and dynamics. However, it is challenging to directly migration (taxis), mechanical damage and repair, endo- measure its properties in cells as a function of time. A plasmic reticulum dynamics, and others. better understanding is needed of ER dynamics, the degradation of which has been linked to neurological The findings from these investigations are applied to disorders including Alzheimer’s disease. To address this design surface-adhered, simple, responsive objects, problem, the group is fabricating an artificial ER-like which are programmable by chemical or physical stim- network, free of proteins and other intracellular ele- uli. These systems may find value in therapeutic appli- ments. To what extent are these dynamics determined cations or for mitigating environmental hazards. by the material properties of the lipid? What is the impact of Ca2+ in the tubular re-arrangements? The group’s artificial system will shed light on these and DESCRIPTION OF THE GROUP’S RESEARCH related questions.

Membrane fractures Biological membranes often form circular pores, but ACHIEVEMENTS IN 2016 they can sometimes break like rigid materials. What determines the pattern formed by a rupturing biomem- Group leader Irep Gözen started in September 2016. brane? Why do these fractures sometimes follow In the short amount of time since the start-up of this dynamics similar to those observed in earthquakes? group, progress has been made on: How can we control pore formation and sealing in the plasma membrane? The group is investigating these and • Receiving external funding related questions. • Initiating plenty of local collaborations • Purchasing and the installation of a state-of-the-art Artificial taxis laser scanning confocal microscope Cell migration can be stimulated by chemicals, tem- perature gradients, and even electromagnetic fields. In Other laboratory-related arrangements and research this project, the group is interested in building cell-like articles are in progress, and interviews regarding hiring constructs which can migrate in response to specific for the Group are also ongoing. environmental cues. Can we build simple, motile lipidic capsules inspired by biological cells? Can these be sensitive to specific compounds in the environment, such as microbial agents, pollutants, or debris in blood vessels? The group’s goal is to engineer programmable structures to achieve this.

CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 45 RESEARCH GROUPS: IREP GÖZEN

Foto: Irep Gözen

FUNDING COLLABORATIONS

In addition to support from NCMM, the Gözen Group Alar Ainla, Harvard University, USA has, in 2016, received additional support from: Vinothan N. Manoharan, Harvard University, USA Michael Taylor, Santa Clara University, USA • Vetenskapsrådet (Swedish Research Council) Aldo Jesorka, Chalmers University, Sweden • Awarded Convergence Environment funding Paul Dommernes, NTNU, Norway from UiO: Life Science. Irep Gözen will lead the Jon Otto Fossum, NTNU, Norway Programmable Cell-like Compartments convergence Marcella Orwick Rydmark, UiO environment. Consortium 1: GROUP MEMBERS Prof. Harald Stenmark, Prof. Andreas Carlson & Dr. Gry Oftedal: UiO: Funding application pending. Expected member: Ilayda Kantarci, Istanbul Technical University (Erasmus Plus Trainee Programme), June- Consortium 2: September 2017 Ute Kengel, Kirsten Sandvig, Michele Cascella & Clare Shelley-Egan: UiO. Funding application pending. Two PhD students, hiring for 2017-2021 in progress One Postdoc, hiring for 2017-2021 in progress. Initially Consortium 3: one year, with the possibility to extend for three more Staale Petter Lyngstadaas, Gry Oftedal, Dirk Linke, years. Employer: Chalmers University, Sweden Reidar Lund & Sandip Kanse: UiO. Funding application pending.

Consortium 4: Sören Abel & Preben Morth: UiO

46 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 NCMM ASSOCIATE INVESTIGATORS AND YOUNG ASSOCIATE INVESTIGATORS

NCMM Young Associate Investigators: NCMM has, through the NCMM Programme for NCMM Associate • Dr. Sören Abel, Department of Pharmacy, University Networking with Associate and Young Associate of Tromsø and Harvard Medical School Investigators, allocated funding for collaborative • Dr. Thomas Arnesen, Department of Molecular projects between NCMM research groups and Associate Biology, University of Bergen and Department of Investigators and Young Associate Investigators. Investigators and Young Surgery, Haukeland University Hospital • Dr. Lorena Arranz, Department of Medical Biology, These grants are designed to act as seed money for new University of Tromsø and Department of Hematology, collaborative projects. Three calls were announced in the University Hospital of Northern Norway (UNN) first five year period of NCMM (2010-2014). A fourth call Associate Investigators • Associate Professor Simona Chera, Department of allocating up to five million NOK was announced at the Clinical Science, University of Bergen end of 2016. • Professor Trude H. Flo, Centre of Molecular NCMM aims to continue and develop its scientific community and knowledge Inflammation Research (CEMIR) and Dept. of Cancer capabilities, through establishing strong collaborative links with key scientists Research and Molecular Medicine, Norwegian University for Science and Technology (NTNU) and research groups across Norway. • Dr. Espen Melum, Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo These links and collaborations greatly support translational networking. University Hospital • Associate Professor Siver Mostue, Department of Circulation and Medical Imaging and Department of Laboratory Medicine, Norwegian University for NCMM’s Associate Investigators Institute of Clinical Medicine, University of Oslo Science and Technology (NTNU) NCMM’s Associate Investigators are drawn from a group • Professor John-Bjarne Hansen, KG Jebsen • Dr. Hege Russnes, Department of Pathology and of outstanding scientists currently based in Norway, – Thrombosis Research and Expertise Centre (TREC), Department of Cancer Genetics, Institute of Cancer with expertise that is compatible with NCMM’s research Department of Clinical Medicine, UiT, The Arctic Research, Oslo University Hospital areas, and who are interested in collaborating with University of Norway and University Hospital of • Dr. Pia Abel zur Wiesch, Department of Pharmacy, NCMM. North Norway University of Tromsø and Yale School of Public Health, • Professor Arne Klungland, Department of Microbiology, US Associate Investigators contribute their expertise in Division of Diagnostics and Intervention, Institute of molecular and translational medicine, and to support Clinical Medicine, Oslo University Hospital and newly recruited young NCMM Group Leaders and Young Institute for Basic Medical Sciences, University of Oslo Associate Investigators through mentoring activities. • Professor Per E. Lønning, Section of Medicine, In 2017, ten new collaborative projects have received funding from NCMM: Grant allocations from NCMM Programme University of Bergen and Department of Oncology, for networking with Associate Investigators and Young Associate Investigators, 2017 Young Associate Investigators Haukeland University Hospital NCMM has initiated a programme for young, talented • Professor Karl-Johan Malmberg, Department of Granted researchers that are recruited as Group Leaders at other Cancer Immunology, Institute for Cancer Research, Associate Investigator(s)/ Collaborating (kNOK) Young Associate Investigator(s) NCMM group(s) this call Project Title institutions. Oslo University Hospital and Institute for Clinical Medicine, University of Oslo Sören Abel Irep Gözen / Preben Morth 700 Dynamics of Protein-Lipid Interaction Young Associate Investigators are recruited through one • Professor Erlend Nagelhus, Department of Molecular of the two following channels: Medicine, Institute of Basic Medical Sciences, Thomas Arnesen Camila Esguerra 300 The physiological impact of N-terminal transferases in 1. Direct application to NCMM in response to open calls University of Oslo and Department of Neurology, Danio rerio – a combined morpholino and inhibitor screen 2. Through universities and other research institutions Oslo University Hospital Lorena Arranz Judith Staerk 650 Mouse xenograft assays to assess the functionality that wish to recruit young, talented Group Leaders • Professor Pål R. Njølstad, KG Jebsen Centre for Diabetes of hESC and iPSC-derived CD34+ cells and where the conditions are similar to those offered Research, University of Bergen and Department of Trude H. Flo Landskron (KT group) 250 Innate immune activation in CD4+ T-cells to NCMM Group Leaders. An affiliation to NCMM can Pediatrics, Haukeland University Hospital Karl-Johan Malmberg Judith Staerk 400 Genetic and functional analysis of hESC then be offered during the call and NCMM will be • Professor Johanna Olweus, KG Jebsen Center for and CD34+-derived blood lineage cells involved in the recruitment process. Cancer Immunotherapy, Department of Cancer Espen Melum Aandahl (KT group) 200 Mucosal associated invariant T-cells during Immunology, Institute for Cancer Research, Oslo bile duct inflammation Associate and Young Associate Investigators continue University Hospital and University of Oslo Erlend Nagelhus Preben Morth 400 Carbonic anhydrase 4 as a drug target to work at their host institutions, but are credited an • Professor Ole P. Rekvig, Department of Medical in neurological disorders with fluid dyshomeostasis affiliation to NCMM and the Nordic EMBL Partnership. Biology, University of Tromsø and University Hospital Hege Russnes Anthony Mathelier 480 The molecular mechanism and impact of transition of Northern Norway from diploid to aneuploid cells in cancer NCMM Associate Investigators: • Professor Anne Simonsen, D epartment of Molecular Anne Simonsen Camila Esguerra 600 Role of NIPSNAP1 in zebrafish development and disease • Professor Lars Akslen, Centre for Cancer Biomarkers Medicine, Institute of Basic Medical Sciences, (CCBIO), University of Bergen and Haukeland University of Oslo Anne Simonsen Preben Morth 500 Structural and functional characterization University Hospital • Professor Anders Sundan, Department of Cancer of Sorting nexin 18 (SNX18) • Professor Ole A. Andreassen, Division of Mental Research and Molecular Medicine, Norwegian Health and Addiction, Oslo University Hospital and University for Science and Technology (NTNU) TOTAL 4480

48 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 49 NCMM ASSOCIATERESEARCH INVESTIGATORS COLLABORATION AND YOUNG WITH OSLOASSOCIATE UNIVERSITYRESEARCH INVESTIGATORS HOSPITAL GROUPS

Research Collaboration with Oslo University Hospital

The overall objectives of NCMM are to conduct cutting-edge research in molecular medicine, and facilitate translation of discoveries in basic medical research into clinical practice. To enable translational research, NCMM has developed strong links to South-Eastern Norway Regional Health Authority and its subsidiary Department of Cancer Genetics, of high international standard. Furthermore, the depart- Institute for Cancer Research (OUH) ment conducts research in most of the areas in which Oslo University Hospital (OUH). NCMM PIs: A. Hurtado, A. Mathelier treatment is provided. The department is organised The main goal of the department is to follow the linear under the Division of Cancer Medicine, Surgery, and time course of predisposition, initiation, early stages and Transplantation at OUH. advanced disease, and to dissect the molecular mechanisms triggered at each stage. Furthermore, the depart- On his appointment to NCMM, Hartmut Luecke will take ment is focusing on how to follow the multi-dimen- up an adjunct position at the Department of Medical sional interactions at various levels in a systems biology Biochemistry as Oslo University Hospital approach to better perform risk estimation, prognostica- All NCMM Translational Research Group Leaders have an extensive research programme, especially related to tion, and prediction. Research Collaborations adjunct positions in clinical or para-clinical departments the diseases HIV/AIDS and hepatitis. The department is with University of Oslo at OUH. Our experience with these affi liations is that also responsible for a variety of advanced educational Institute for Experimental Medical Research (OUH) All NCMM Biotechnology Group Leaders hold adjunct they facilitate clinical collaborations, give group leaders courses in infectious diseases and is organised under the NCMM PI: J. P Morth positions at the following departments: better access to patient materials, biobanks and clinical Medicine Division at OUH. The Institute for Experimental Medical Research primar- trials, and that they are crucial to facilitate translational ily focuses on heart disease research and teaching. In School of Pharmacy research. These research collaborations have already Department of Molecular Oncology, particular, the institute performs research on congestive Camila Vicencio Esguerra resulted in a number of joint publications. NCMM Group Institute for Cancer Research (OUH) heart failure, with a special interest in heart electrophys- Leaders also report on several joint applications for fund- NCMM PI: I. Mills iology and membrane pumps. The institute is involved Department of Chemistry ing of new collaborative projects. The Institute for Cancer Research has strong interna- in extensive collaborations with other laboratories in Irep Gözen and Nikolina Sekulic tional research groups within biochemistry, cell and clinical departments at the OUH, and interacts with NCMM Group Leaders currently hold adjunct appoint- tumour biology, genetics, radiation biology, immunology, colleagues nationally and internationally. The institute Department of Biosciences ments at the following departments: and cancer prevention. For more than 30 years there has is organised under the Division of Cardiovascular and Sandra Avilez-Lopes been a close interaction between researchers at this insti- Pulmonary Disease at OUH. Department of Infectious Diseases (OUH) tute and cancer surgeons, oncologists, and pathologists. NCMM PI: K. Taskén The emphasis on translational science has resulted in Department of Haematology, (OUH) The department is the largest of its kind in Norway. It numerous clinical protocols based on in-house research NCMM PI: J. Staerk covers the entire fi eld of infectious medical conditions, and the institute is a key partner in the Comprehensive Patients with all types of blood diseases are treated at the such as tropical medicine, HIV, and tuberculosis, as Cancer Centre, organisationally under the Division of Department of Haematology. The department’s goal is to well as severe and life threatening bacterial and viral Cancer Medicine, Surgery and Transplantation at OUH. deliver excellent patient care, provide advanced teach- infections. The Department of Infectious Diseases runs ing in the fi eld of blood diseases and perform research

50 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 51 RESEARCH HIGHLIGHTS From Disease Mechanisms Research to Clinical Practice Highlights

NCMM group leaders have so far listed some 27 on-going operational and Study into effects of aspirin on colorectal cancer The interplay between TORC1 and TORC2 complexes, patients with liver metastases and their role in processing nutritional cues to interventional clinical studies in the fields of therapy and disease mechanisms as regulate cellular behaviour well as in the molecular markers, diagnostic and monitoring areas. As reported in the 2015 NCMM Annual Report, a study by NCMM’s Taskén Group into how aspirin affects the Growing cells integrate a variety of cues in order to survival rates of patients with colorectal cancer (CRC), decide whether conditions are favourable for cell divi- was published in the Journal of Clinical Oncology. sion, or whether they have to halt their cell cycle and On-going development in the area of therapy On-going development in the area of diagnostics and differentiate. Failure to do so has negative implications in • Immunomodulating cAMP antagonists and PKA monitoring The paper, with Simer J. Bains as first author and the fitness of the organism. For example, cancer patho- anchoring disruptors (immunodeficiency and anti-tu- • Prostate cancer markers – serum/plasma protein bio- Kjetil Taskén as last author, presented the data from genesis is often associated with the poor capacity of can- mor immune responses). markers, overlapping genetic risk factors for prostate a large cancer registry study that coupled data with cer cells to differentiate. • Disruption of the PKA-AKAP18-phospholamban- cancer and blood lipid traits, transcript-based biomark- the Norwegian Cancer Registry and the Norwegian Serca2 complex for cardio-protective effect in isch- ers in urine and circulating tumor cells. Evaluation of Prescription Database. It was found that aspirin expo- emia-reperfusion damage. protein biomarkers in blood samples from patients sure after diagnosis of CRC was independently associ- • Small molecule inhibitors of OGlcNAc tranferase and with prostate cancer undergoing radiotherapy with or ated with an improved survival rate of colorectal can- de novo purine biosynthesis enzymes to destabilize without androgen deprivation therapy. Further evalu- cer-specific survival, as well as overall survival. oncogenic signaling in prostate cancer. ation of blood-based protein biomarkers in relation to • Bromodomain inhibition to enhance responses to outcomes from surgery and radiotherapy. CRC affects around 4000 people in Norway each year, androgen deprivation/anti-androgens in prostate • New biochemical markers for MAO diseases & early and half of these patients will see the cancer spread to cancer. screen Parkinson. their liver. • Targeting of Na+/K+-ATPase and Serca2 in neurobiol- • Single cell analysis of inflammatory signaling events by ogy and heart disease. fluorescent cell bar-coded phospho-flow cytometry for The findings from the initial retrospective study by Bains • Suppression mechanisms by regulatory T cells with diagnostics and monitoring et al were such that a new multicentre, intervention application in immune diseases, autoimmunity and • Regulatory T cell markers in HIV and other immune study has been initiated to explore the effects of aspirin cancer. diseases. on patients suffering from CRC that have also had surgi- • iPSC disease-modeling of blood disorders. • Flow cytometry-based biomarkers in mitogenic signal- cally-remove liver metastases. • Assay development and structural analysis of the mem- ing pathways for drug sensitivity screens. brane proteins in virulence operon mgtCBR specific to • Signalling responses in peripheral T cells from colorec- 19m NOK has been awarded to the project by pathogenic bacteria. tal cancer patients are affected by high concentrations KLINBEFORSK (Department of Health and Social Figure legend: Graphical Abstract • Structural analysis of the membrane proteins linked of circulating prostaglandin E2. Services) for 2017-2021, alongside 12m NOK funding to the virulence operon mgtCBR specific to pathogenic • Ongoing observational study on chronic lymphatic leu- from the Cancer Society and The Research Council of The TORC1 and TORC2 complexes play important roles bacteria. kaemia (CLL) and multiple myeloma (MM). Norway. in integrating nutritional cues to activate transcriptional • Structural analysis of bicarbonate transporters and • Observational studies on asthma and chronic obstruc- programmes and thereby regulate cellular behaviour. investigation of pH homeostasis tive lung disease inflammatory component. NCMM Director Kjetil Taskén will co-lead the study, However, the interplay between these complexes has, • Enzymatic detection and quantification assay of isatin, • Observational studies on HIV long-term non-responders. alongside Bjørn Atle Bjørnbeth at Oslo University until now, been poorly understood. To address this a putative stress biomarker in blood. • Interventional study on COX-2i and vaccine in TB Hospital and Sheraz Yaqub at UiO. issue, Lopez-Aviles and colleagues used the fission yeast • Investigation of the Membrane-associated RING finger patients. Schizosaccharomyces pombe to investigate how phos- protein (MARCH) E3-ligases. Around 700 patients will be observed in the study; phatase activity participates in the interplay between • Cancer drug sensitivity screening on patient samples Proof-of-concept in humans around half will take aspirin each day with the other half the TORC1 and TORC2 complexes during the switch from with set of approx. 400 cancer drugs to assist clinical • Effect of anti-inflammatory drug (COX-2 inhibitor receiving a placebo. The study aims to explore whether proliferation to sexual differentiation. decision on individualized therapy choices in chronic Phase IIA) on immune function (CD38 o.a.) and vaccine aspirin use has an impact on the survival rates of those lymphatic leukemia, multiple myeloma and ovarian responses in HIV-infected patients. (Recent publication, prescribed aspirin. Lopez-Aviles and colleagues found that loss of the phos- cancer. Prebensen et al. May 2017). phatase PP2A-B55Pab1 enhances the expression of dif- • Elucidation of the mechanism of action of medrox- • Secondary preventive effect of acetyl salicylic acid in All Norwegian university hospitals that treat patients with ferentiation-specific genes and leads to premature con- iprogesterone injection before surgery as a treatment metastatic colorectal cancer. CRC that has spread to the liver will participate, including: jugation. Deletion of pab1 brings about a transcriptional that improves overall and disease-free survival of ER+/ Oslo University Hospital profile similar to TORC1 inactivation, and also overcomes HER2- breast cancer patients. Furthermore, NCMM is involved in two translational KG Stavanger University Hospital the repression of differentiation genes in cells overex- • Development of CAMKK2 inhibitors for the treatment Jebsen Research Centres that were established in 2013. University Hospital of North Norway Tromsø pressing TORC1. Importantly, it was possible to show of prostate cancer. NCMM is connected to the KG Jebsen Centres Inflammation St. Olav’s Hospital in Trondheim that this effect is mediated by an increased TORC2-AKT Research (led by Prof. Guttorm Haraldsen) and Cancer Haukeland University Hospital in Bergen (Gad8) signalling. Immunotherapy (led by Prof. Johanna Olweus).

52 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 53 RESEARCH HIGHLIGHTS

Under nutrient-rich conditions, PP2A-B55Pab1 dephos- observed that the chromatin loops formed when cells are phorylates Gad8 Ser546, repressing its activity. treated with estrogen establish contacts with the nuclear Conversely, TORC1 inactivation upon starvation leads to lamina. Once there, the portion of CTCF associated with the inactivation of PP2A-B55Pab1 through the Greatwall- the nuclear lamina interacts with enhancer regions, Endosulfin pathway. This results in the TORC2-mediated limiting the formation of ER loops and the induction of activation of Gad8 and the commitment to differentia- genes present in the loop. tion. In summary, PP2A-B55Pab1 enables a crosstalk between the two TOR complexes that controls cell-fate Collectively, results from the Hurtado Group’s research decisions in response to nutrient availability. reveal an important, unanticipated interplay between CTCF and nuclear lamina to control the transcription In the future, more exhaustive studies of PP2A-B55Pab1 of ER target genes, which has great implications in the and Gad8 targets will be fundamental to understand rate of growth of breast cancer cells. CTCF emerges as how these signalling nodes modulate the differentiation a new player in the intricate network of transcription process. factors regulating gene expression during breast cancer progression. The full article, A PP2A-B55-Mediated Crosstalk between TORC1 and TORC2 Regulates the Differentiation Response The full article, CTCF modulates Estrogen Receptor in Fission Yeast, can be found in Current Biology 2017 Jan function through specific chromatin and nuclear matrix 23; 27(2): 175–188. doi: 10.1016/j.cub.2016.11.037 interactions, can be found on Nucleic Acids Research, 2016, 44 (22): 10588-10602. DOI: https://doi.org/10.1093/ nar/gkw785 CTCF emerges as a new player in transcription factors regulating gene expression during breast cancer progression Top talent recruited to NCMM

This study from the Hurtado Group reveals an important, NCMM has significantly added to its breadth of research unanticipated interplay between the transcriptional reg- expertise with the appointment of three new, young ulator CCCTC-binding factor (CTCF) and nuclear lamina Group Leaders and a new Assistant Director. that control the transcription of ER target genes. CTCF is Nikolina Sekulic, Irep Gözen, and Anthony Mathelier all an ubiquitous multivalent zinc finger protein that regu- joined the Centre in 2016. lates higher-order chromatin organisation. Here, Hurtado and colleagues show that CTCF plays an Nikolina Sekulic was recruited from the lab of Professor active role in moderating gene transcription induced by Ben Black at the University of Pennsylvania in January, estrogen through its direct interaction with transcrip- and has set up the Structural Biology and Chromatin tionally active chromatin-regions. Group. Dr. Sekulic’s previous work in Pennsylvania has set the foundation for biochemical understanding of cen- Enhancer regions and transcription start sites of estro- tromeres by providing the first high-resolution structure gen-target regulated genes are connected by means of of specialised histone (CENP-A) that is defining these Estrogen Receptor (ER) long-range chromatin interac- chromosome loci. tions. Yet, the complete molecular mechanisms controlling the transcriptional output of engaged enhancers Anthony Mathelier was recruited from the group of Dr. and subsequent activation of coding genes remain elusive. Wyeth Wasserman at the University of British Columbia, Vancouver, Canada, where he was deputy group leader. Hurtado and colleagues have found that CTCF binding Anthony started in May 2016 and is now the Group Leader migration (taxis), mechanical damage and repair, endo- will add further excellence to the quality of basic biolog- to enhancer RNAs is enriched when breast cancer cells of the Computational Biology and Gene Regulation Group plasmic reticulum dynamics, and others. ical research conducted at both NCMM, and in the wider are stimulated with estrogen. CTCF binding to enhancer at NCMM. The Mathelier Group develops and assesses context of the Nordic EMBL Partnership. regions results in modulation of estrogen-induced gene computational methods to analyse genomic sequences Additionally, as discussed earlier in this annual report, transcription by preventing ER chromatin binding and (DNA). The goal of the group is to create the next genera- the appointment of NCMM Assistant Director, Professor by hindering the formation of additional enhancer-pro- tion of cutting-edge algorithms and open computational Hartmut Luecke, (due to officially join NCMM in moter ER looping. biology software, with immediate application to real-life November 2017), from University of California, Irvine, biological problems. USA, will contribute hugely to the structural biology Furthermore, the depletion of CTCF facilitates the community in Oslo. expression of target genes associated with cell division Irep Gözen was recruited from the Manoharan Lab at and increases the rate of breast cancer cell proliferation. Harvard University to set up the Bionanotechnology The recruitment and appointment of these four extremely Hurtado and colleagues have also uncovered a genomic and Membrane Systems Group. Dr. Gözen started in talented researchers to NCMM further strengthens our network connecting loci enriched in cell cycle regulator September 2016 and the group uses soft biomaterials, status as a greenhouse for the nurturing and develop- genes to nuclear lamina that mediates the CTCF function. such as lipid membranes, to mimic the behaviour of ment of international research talent. living cells. By modelling a complex cell with minimal The nuclear lamina and chromatin interactions are forms in experiments, the group aims to gain a deeper All four have been recruited back to Europe from the regulated by estrogen-ER. Hurtado and colleagues have understanding of certain biological processes, including USA and Canada, and they and their research groups

54 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 55 News and events NEWS AND EVENTS

NCMM Network Meeting The inaugural NCMM Network meeting took place and Young Associate Investigators, Board members, and in January. The meeting was aimed at NCMM Group other stakeholders and scientific leaders. Leaders, newly and re-appointed Associate Investigators

NCMM Network Meeting 2016. Photo: Johannes Landskron, NCMM

JANUARY 2016 JUNE

King Olav V Prize for Cancer Research 2016

From the left: The Secretary General of the Norwegian Cancer Society Anne Lise Ryel, HM King Harald V, Prof. Kjetil Taskén and Gunn- Elin Aa Bjørneboe (Chair, Board Cancer Society). Photo: Kreftforeningen

NCMM Director, Professor Kjetil Taskén, received the standing of immuno-oncology; work which is highly The Nordic EMBL Partnership Meeting. Photo: EMBL prestigious King Olav V’s Prize for Cancer Research 2016 relevant in the development of next-generation of during a special ceremony at the University of Oslo on immunotherapy. June 6 2016. Nordic EMBL Partnership King Olav V’s Cancer Research Fund, and its associated The Nordic EMBL Partnership Conference, ‘Perspectives The prize was presented by King Harald V at the prize, was established in memory of King Olav V in 1992. in Translational Medicine’ and EMBL Steering Committee University of Oslo’s Gamle Festsal, on behalf of the Since then the prize has been awarded every year to an meeting took place at the EMBL headquarters in Heidelberg Norwegian Cancer Society. outstanding researcher who has distinguished them- in June. The three-day meeting involved the other Nordic selves by working to improve the lives of many people. EMBL Partners, FIMM, MIMS, and DANDRITE, plus other Professor Taskén was awarded the highly-coveted prize EMBL Partners from across Europe. in recognition of his major contribution to the under- The prize is 1 million NOK.

56 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 57 NEWS AND EVENTS NEWS AND EVENTS

SAB Visit Scientific Retreat The Scientific Advisory Board (SAB) visited NCMM in NCMM and the BiO organized a joint scientific retreat to October for their fifth visit. the Holmen Fjordhotell for all employees and students. The two-day retreat included scientific talks and discussions, a social dinner, and outdoor activities.

The merger between NCMM and BiO was formally NCMM Network Meeting completed at the start of January. The Second NCMM Network Meeting took place This marks an exciting development for the Network, at Forskningsparken. bringing together two centres with a shared model. The merger means NCMM is now home to 11 research groups. Holmen Fjord Hotell

OCTOBER NOVEMBER JANUARY - FEBRUARY 2017 MARCH MAY PHOTO: JOHANNES LANDSKRON

Convergence Environment Funding NCMM Director Kjetil Taskén and Group Leader Irep Gözen awarded Convergence Environment funding from UiO: Life Science. Irep Gözen will lead the Programmable Cell Like Compartments Convergence Environment, and Kjetil Taskén will be a co-PI for the Personalised Cancer Therapies (PERCATHE) Convergence Environment led by Arnoldo Frigessi.

Professor Per O. Seglen with Anne Lise Ryel, General Secretary of National PhD Course Molecular Medicine the Norwegian Cancer Society. Foto: Ingvild Vaale Arnesen/Kreftforeningen NCMM organized a national PhD course in molecular medicine in November. Altogether, 35 participants from differ- King Olav V Prize for Cancer Research ent institutions in Norway attended this two-week course. NCMM Guest Researcher, Professor Per O. Seglen, was The aim of the course is to give participants insights into announced as the winner of the 2017 King Olav V’s the translational and clinical aspects of science. Prize for Cancer Research. Professer Seglen has been awarded the prize in recognition of his pioneering work with autophagy. The prize will be presented in a ceremony on 6 June 2017.

58 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 59 NCMM PhD dissertations NCMM has recruited an international group of PhD fellows, and in 2016 nine PhD candidates from seven different countries defended their thesis at UiO.

SIMER J. BAINS THEIS SOMMER MD Simer J. Bains defended her thesis MSc Theis Sommer defended his thesis entitled “Malignancy, Metastasis and “Biotechnological application and bio- Immune Modulation – Experimental physical characterization of the bacterial Tumor Immune Regulation and Obser- enzyme Isatin hydrolase AND Structural vational Clinical Studies in Ovarian and studies of the regulatory N-terminal Colorectal Cancer” in January 2016. The domain of the SLC4 bicarbonate trans- work was performed in the research porter family and characterization of a group of Kjetil Taskén, and Bains defended novel zinc binding,” at the Department her thesis at the Faculty of Medicine, UiO. of Biosciences, Faculty of Mathematics and Natural Sciences, UiO in June 2016. The research was carried out in the ELISA FIORITO research group of Jens Preben Morth. NCMM’s Elisa Fiorito defended her thesis entitled “Study of the role of CTCF and FOXA1 Attendees at the in breast cancer” in April 2016 at the ALEKSANDRA DUKIC NCMM Network meeting. Department of Biosciences, Faculty of Aleksandra Dukic defended her the- Photo: Johannes Landskron, Network Meeting 2017 Mathematics and Natural Sciences, UiO. sis “Role of protein kinase A and the NCMM Fiorito’s research was performed in the A-kinase anchoring protein Ezrin in reg- research group of Antoni Hurtado. ulation of gap junction communication” at Faculty of Medicine, UiO, in December 2016. The research was carried out in SARANYA SUBRAMANI the research group of Kjetil Taskén. Saranya Subramani defended her thesis Centre for Molecular Medicine Norway (NCMM) held The programme: Day One entitled “Biochemical character-ization its annual Network Meeting at Oslo Science Park over 6 The fi rst day of the meeting included talks from and crystallization of the magnesium LISA GERNER and 7 February. NCMM Associate Investigators (AIs), Young Associate transporting P-type ATPase MgtA” in Lisa Gerner defended her thesis entitled Investigators (YAIs), and Group Leaders. Topics covered May 2016. The work was carried out in “An Exploration of the Structure and The Network Meeting brings together the scientifi c ranged from the Nobel Prize in Chemistry to in-depth the research group of Jens Preben Morth, Function of Calcium/calmodulin-de- NCMM network from all over Norway, as well as Board insights into current research at NCMM. and Subramani defended her thesis pendent kinase kinase 2 (CaMKK2) members and other stakeholders. The meeting provides at the School of Pharmacy, Faculty of in Prostate Cancer” at the Faculty a setting where all members have the chance to catch The day rounded off with three panel debates, covering Mathematics and Natural Sciences, UiO. of Medicine, UiO, in February 2017. up and share their expertise, news, and thoughts on the topics such as personal career experiences, genomic Gerner’s work was carried out in the research landscape. medicine and gene-editing, and drug repurposing and research groups of Ian G. Mills and Jens personalized cancer treatment. STALIN CHELLAPPA Preben Morth. Following on from 2016’s inaugural Network Meeting, GUNASEKARAN where several outside speakers presented on more gen- Stalin Chellappa Gunasekaran defended eral topics, 2017’s invite-only event mostly saw speakers The programme: Day Two his thesis entitled “Human Regulatory T BERTRAND SIMON from within the NCMM network, giving more in-depth Day Two of the event was open only to NCMM Group cells: Suppressive Function and Role in Bertrand Simon, a joint student from the EMBL outsta- talks about their research and the landscape as a whole. Leaders and Associate and Young Associate Investigators. Pancreatic Cancer and Distal Bile Duct tion in Hamburg and NCMM, defended his thesis entitled Cancer” in June 2016. The work was “Structural and functional regulation of death-associated NCMM has allocated up to 5 million NOK for funding completed in the research group of Kjetil protein kinases activity by calcium/calmodulin binding”. concrete collaborative projects between NCMM Group Taskén, and Gunasekaran defended his Simon’s research was carried out under the supervision of Leaders and AIs/YAIs. This day focused more on allow- thesis at the Faculty of Medicine, UiO. Ian G. Mills at NCMM and Professor Matthias Wilmanns ing Group Leaders to connect with AIs and Young AIs, at EMBL-Hamburg. and to try and fi nd some common ground where collaboration might be interesting. The day included elevator NORA V. LIESKE pitch sessions, which led on to an informal ‘speed-dat- M.Sc. Nora Valeska Lieske defended her ing’ session. thesis, “Modulation of Adaptive Immune Responses — Studies in infectious dis- NCMM would like to thank everyone who attended and eases and immune disorders” in June we look forward to welcoming you again for an exciting 2016. The work was performed in the event in 2018. research group of Kjetil Taskén, and Lieske defended her thesis at Faculty of A panel debate at the NCMM Network meeting. Medicine at UiO. Photo: Johannes Landskron, NCMM

60 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 61 NCMMNCMM ASSOCIATE Board INVESTIGATORS AND YOUNG ASSOCIATERESEARCH INVESTIGATORS GROUPS

Chair Ragnhild A. Lothe: “The Board is pleased with the decision to merge NCMM and BiO (Biotechnology Centre of Oslo), which was formally put into effect on the 2nd January 2017.” Chair of the NCMM Board, Ragnhild A. Lothe with NCMM Director Kjetil Taskén BOARD MEMBERS The Centre now hosts two departments: NCMM Translational research and NCMM Biotechnology, with a total The NCMM Board is responsible for, in collaboration Chair: of 11 independent groups ensuring less vulnerability for the Centre with the Director, the Centre’s overall coordination Professor Ragnhild A. Lothe, Oslo University Hospital and progress. The Board steers and supervises NCMM’s (OUH) and University of Oslo (UiO) as a whole. However, it remains a challenge for new group leaders activities and fi nances and also approves the Centre’s to become fully integrated in the scientifi c community of Oslo within strategic plans, objectives and budget. Members: a reasonable time frame. A challenge we all may contribute to solve. Professor Jan G. Bjålie, Faculty of Medicine, UiO The Board’s decisions contribute to promoting excel- Professor Finn-Eirik Johansen, Faculty of Mathematics lence in the Centre’s recruitments, research, collabora- and Natural Sciences, UiO The Board congratulates professor Kjetil Taskén who received the tions, and translational value. Director Research and Innovation Per Morten Sandset, King Olav V’s Prize for Cancer Research in June 2016 in recognition South-Eastern Norway Regional Health Authority (HSE) The Board consists of the Chair and fi ve members rep- Professor Jens Petter Berg, Oslo University Hospital of his, “major contribution to the understanding of immuno-oncology”. resenting NCMM’s host, the University of Oslo and the Maria Perander, UiT The Arctic University of Norway Work that will become even more relevant in the development of consortium partner Health South-East Regional Health (national representative) next-generation immunotherapy. Authority (HSE), as well as a national representative. Deputy Members: Professor Hilde Nilsen, Faculty of Medicine, UiO and Furthermore, we also congratulate Professor Emeritus Per Seglen Akershus University Hospital at NCMM, who will receive the King Olav V’s Prize for Cancer Head of Research Øystein Krüger, Dept. of Research Research June 2017. This is very well deserved for his ground- and Innovation, South-Eastern Norway Regional Health Authority (HSE) breaking research into autophagic-lysosomal protein degradation Professor Ola Myklebost, and its relationship to cancer. University of Bergen (national representative)

62 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 63 PHOTO: JOHN HUGHES

NCMM Funding

NCMM is in its second five-year period. NCMM core The decrease in extramural funding in 2016 compared funding in this period is 31 million Norwegian kroner to the last couple of years is a result of research groups (mNOK) per year from the three consortia partners; rotating out of the Centre in the period 2014-2016. In UiO, the Research Council of Norway (RCN), and Health 2016 three new research groups were recruited to SouthEast (HSE). Including transferred funds, NCMM NCMM/BiO, and another group will be established in spent 30 mNOK in 2016. This was less than budgeted the fall of 2017. We therefore expect the amount of and was due to some delays in recruitment of a new extramural funding to increase again from 2018 as the research group/assistant director. new groups become more established.

In January 2017, the merger between NCMM and the Extramural funding for 2017 is so far stipulated to 36 Biotechnology Centre of Oslo (BiO) formally came into mNOK. In addition, NCMM’s Director is Co-PI on two effect. The new NCMM consists of two departments: clinical intervention trials where the funding is placed NCMM Translational Research (former NCMM) and at the Oslo University Hospital. In 2017 these projects NCMM Biotechnology (former BiO) with altogether have been funded with altogether 8.75 mNOK from the 11 research groups. The core funding for NCMM Research Council of Norway, The Norwegian Cancer Translational Research in 2017 is, as before, 31 mNOK Society, and the Norwegian Department of Health and per year, whereas NCMM Biotechnology has a core Social Services. funding of 27.2 mNOK. Furthermore, overheads, income Scientific Advisory from core facilities, and production-based income are in addition.

NCMM extramural funding, in the form of grants to 23% Board (SAB) the group leaders and other competitive funding, has increased steadily from 7 mNOK in 2010 to 42 35% UIO mNOK in 2015. In 2016, NCMM reached 32 mNOK in RCN annual grants. This includes grants from the Research NCMM HSE The NCMM Scientific Advisory Board (SAB) was Professor Richard Treisman – Chair from March 2017 Council of Norway, the Norwegian Cancer Society, Core Funding first appointed in 2011 and, from 2015, the SAB was Director of CRUK London Research Institute Health SouthEast, competitive grants at UiO, European also appointed as a joint Board for NCMM and the London, UK Commission, and private foundations and organisa- 2016 Biotechnology Centre of Oslo, an agreement which will Research Director, the Francis Crick Institute tions such as the Lundbeck Foundation, Novo Nordisk UIO continue. London, UK Foundation, KG Jebsen Centres, amongst others. RCN 42% The SAB’s main mission is to offer academic and stra- Professor Erich Nigg HSE tegic advice, as well as benchmark the performance of Director of Biozentrum NCMM’s research groups and the Centre internation- Basel, Switzerland ally. The SAB meets with NCMM core members every 12-24 months. These meetings allow for review of recent Dr. Alvis Brazma progress and advice on future strategies. EMBL Senior Scientist & Senior Team Leader EMBL-EBI Hinxton The previous SAB visit took place in the autumn of 2016, Cambridge, UK and the next visit is expected to take place in autumn 2017. 7% Professor Margaret Frame 3% RCN Members of NCMM’s Scientific Advisory Board Science Director and Chair of Cancer Biology 6% 5% 5% The SAB consists of six internationally Edinburgh Cancer Research Centre UIO 5% RCN renowned scientists: Edinburgh, UK 34% RCN UIO HSE Extramural UIO Estimated Extramural 14% HSE Professor Lief Groop (Chair) – until March 2017 Professor Nazneen Rahman Funding Sources HSE Funding Sources 21% The Norwegian Cancer Society 46% The Norwegian Cancer Society Head of Lund University Diabetes Centre Head of Division of Genetics and Epidemiology The Norwegian Cancer Society Other national grants Other national grants Department of Endocrinology Institute of Cancer Research 2016 EU Grants 2017 Other national grants Clinical Sciences Malmø London, UK Other international grants EU Grants Other international grants Lund University, Sweden EU Grants 16% 14% Professor Olli Kallioniemi (from March 2017) 13% Director SciLifeLab Other international grants Stockholm, Sweden 11%

The 2017 overview is an estimate of extramural funding sources based on budget and on secured grants.

64 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 65 NCMM-Affiliated NCMM-AFFILIATED PUBLICATIONS Fiorito, Elisa; Sharma, Yogita; Gilfillan, Siv; Wang, Pedersen, Jan Skov; Morth, Jens Preben; Andreasen, Peter A.; Shixiong; Singh, Sachin Kumar; Somisetty, Venkata Jensen, Jan Kristian. Satheesh; Madhumohan, Katika; Urbanucci, Alfonso; Crystal structure of a Two-domain fragment of hepato- Publications 2016 Thiede, Bernd; Mills, Ian Geoffrey; Rodriguez, Antoni cyte growth factor activator inhibitor-1. Hurtado. Journal of Biological Chemistry 2016 ;Volum 291.(27) CTCF modulates Estrogen Receptor func- s.14340-14355 Arenillas, David J.; Forrest, Alistair R.R.; Kawaji, Hideya; Overview of the membrane-associated RING-CH tion through specific chromatin and nuclear Lassmann, Timo; Wasserman, Wyeth W.; Mathelier, (MARCH) E3 ligase family. New Biotechnology 2016 matrix interactions. Itkonen, Harri; Gorad, Saurabh Sayajirao; Duveau, Anthony. Nucleic Acids Research 2016 ;Volum 44. s.10588-10602 Damien Y.; Martin, Sara E.S.; Barkovskaya, Anna; Bathen, CAGEd-oPOSSUM: Motif enrichment analysis from Bjerregaard-Andersen, Kaare; Østensen, Ellen; Scott, Tone Frost; Moestue, Siver Andreas; Mills, Ian Geoffrey. CAGE-derived TSSs. John D.; Tasken, Kjetil; Morth, Jens Preben. Gerner L, Munack S, Temmerman K, Lawrence-Dorner Inhibition of O-GlcNAc transferase activity reprograms Bioinformatics 2016 ;Volum 32.(18) s.2858-2860 OUS UiO Malonate in the nucleotide-binding site traps human AM, Besir H, Wilmanns M, Jensen JK, Thiede B, Mills IG prostate cancer cell metabolism. AKAP18/ in a novel conformational state. and Morth JP. OncoTarget 2016 ;Volum 7.(11) s.12464-12476 Asim, Mohammad; Massie, Charles E.; Orafidiya, Acta Crystallographica. Section F : Structural Biology Data for the co-expression and purification of human Folake; Pértega-Gomes, Nelma; Warren, Anne Yvonne; and Crystallization Communications 2016 ;Volum 72. recombinant CaMKK2 in complex with calmodulin in Leo, Jack Christoffer; Oberhettinger, Philipp; Yoshimoto, Esmaeili, Mohsen; Selth, Luke A.; Zecchini, Heather I.; s.591-597 Escherichia coli. Data Brief. 2016; 8:733-740. Shogo; Udatha, D.B.R.K. Gupta; Morth, Jens Preben; Luko, Katarina; Qureshi, Arham; Baridi, Ajoeb; Menon, Schutz, Monika; Hori, Katsutoshi; Linke, Dirk. Suraj; Madhu, Basetti; Escriu, Carlos; Lyons, Scott K.; Chelappa, S; Lieske, N.V; Hagness, M; Line, P.D; Taskén, Gerner, Lisa; Munack, Steffi; Temmerman, Koen; Secretion of the Intimin passenger domain is driven by Vowler, Sarah L.; Zecchini, Vincent R.; Shaw, Gregory K; Aandahl, E.M Lawrence-Dörner, Ann-Marie; Besir, Huseyin; Wilmanns, protein folding. Journal of Biological Chemistry 2016; L.; Hessenkemper, Wiebke; Russell, Roslin; Mohammed, Human regulatory T cells control TCR signalling and sus- Matthias; Jensen, Jan Kristian; Thiede, Bernd; Mills, Ian Volum 291.(38) s.20096-20112 Hisham; Stefanos, Niki; Lynch, Andrew G.; Grigorenko, ceptibility to suppression in CD4+ T cells. Geoffrey; Morth, Jens Preben. Elena; D’Santos, Clive; Taylor, Christopher; Lamb, Journal Leukocyte Biology., 100:5-16, In section “Spotlight Using the fluorescent properties of STO-609 as a tool Leroy, Emilie; Defour, Jean-Philippe; Sato, Takeshi; Dass, Alastair; Sriranjan, Rouchelle; Yang, Jiali; Stark, Rory; on Leading Edge Research”, Editorial: Jeschke & Williams. to assist structure-function analyses of recombinant Sharmila; Gryshkova, Vitalina; Shwe, Myat; Staerk, Dehm, Scott M.; Rennie, Paul S.; Carroll, Jason S.; Griffiths, Treg potency and the importance of being fit. Ibid, 1-3. CaMKK2. Judith; Constantinescu, Stefan N; Smith, Steven O. John R.; Tavaré, Simon; Mills, Ian Geoffrey; McEwan, Iain Biochemical and Biophysical Research Communications His499 Regulates Dimerization and Prevents Oncogenic J.; Baniahmad, Aria; Tilley, Wayne D.; Neal, David E.. Cieslar-Pobuda, Artur; Rafat, Mehrdad; Knoflach, - BBRC 2016 ;Volum 476.(2) s.102-107 Activation by Asparagine Mutations of the Human Choline Kinase Alpha as an Androgen Receptor Viktoria; Skonieczna, Magdalena; Hudecki, Andrzej; Giordano, Cinzia; Chemi, Francesca; Panza, Salvatore; Thrombopoietin Receptor. Chaperone and Prostate Cancer Therapeutic Target. Malecki, Andrzej; Urasinska, Elzbieta; Ghavami, Seaid; Barone, Ines; Bonofiglio, Daniela; Lanzino, Marilena; Journal of Biological Chemistry 2016 ;Volum 291.(6) Journal of the National Cancer Institute 2016 ; Los, Marek J. Cordella, Angela; Campana, Antonella; Hashim, Adnan; s.2974-2987 Volum 108 (5) Human induced pluripotent stem cell differentiation and Rizza, Pietro; Leggio, Antonella; Gyorffy, Balazs; Simoes, Liu, Lisa L.; Landskron, Johannes; Ask, Eivind Heggernes; direct transdifferentiation into corneal epithelial-like Bruno M; Clarke, Robert B.; Weisz, Alessandro; Catalano, Enqvist, Monika; Sohlberg, Ebba; Traherne, James A.; cells. Stefania; Ando, Sebastiano. Hammer, Quirin; Goodridge, Jodie; Larsson, Stella; OncoTarget 2016 ;Volum 7.(27) s.42314-42329 Leptin as a mediator of tumor-stromal interactions Jayaraman, Jyothi; Oei, Vincent Yi Sheng; Schaffer, Marie; promotes breast cancer stem cell activity. Tasken, Kjetil; Ljunggren, Hans-Gustaf; Romagnani, Dukic, Aleksandra; McClymont, David; Tasken, Kjetil. OncoTarget 2016 ;Volum 7.(2) s.1262-1275 Chiara; Trowsdale, John; Malmberg, Karl-Johan; Béziat, A Cell-Based High-Throughput Assay for Gap Junction Vivien. Communication Suitable for Assessing Connexin Gunasekaran, Stalin Chellappa; Hugenschmidt, Harald; Critical Role of CD2 Co-stimulation in Adaptive Natural 43-Ezrin Interaction Disruptors Using IncuCyte ZOOM. Hagness, Morten; Line, Pål Dag; Labori, Knut Jørgen; Killer Cell Responses Revealed in NKG2C-Deficient Journal of Biomolecular Screening 2016 Wiedswang, Gro; Tasken, Kjetil; Aandahl, Einar Martin. Humans. Regulatory T cells that co-express RORt and FOXP3 are Cell reports 2016 ;Volum 15.(3) s.1088-1099 pro-inflammatory and immunosuppressive and expand in human pancreatic cancer. Lorvik, Kristina Berg; Hammarström, Clara Louise; Oncoimmunology 2016 ;Volum 5.(4) Fauskanger, Marte; Haabeth, Ole Audun; Zangani, Michael M; Haraldsen, Guttorm; Bogen, Bjarne; Corthay, Gunasekaran, Stalin Chellappa; Lieske, Nora Valeska; Alexandre. Bains, Simer Jit; Mahic, Milada; Myklebust, Tor Åge; Hagness, Morten; Line, Pål Dag; Tasken, Kjetil; Aandahl, Adoptive transfer of tumor-specific Th2 cells eradicates Småstuen, Milada C; Yaqub, Sheraz; Dørum, Liv Marit; Einar Martin. tumors by triggering an in situ inflammatory immune Bjørnbeth, Bjørn Atle; Møller, Bjørn; Brudvik, Kristoffer Human regulatory T cells control TCR signaling and sus- response. Watten; Tasken, Kjetil. ceptibility to suppression in CD4+ T cells. Cancer Research 2016;Volum 76.(23) s.6864-6876 Aspirin as secondary prevention in patients with colorec- Journal of Leukocyte Biology 2016 ;Volum 100.(1) s.5-16 tal cancer: An unselected population-based study. Lizio, M; Harshbarger, J; Abugessaisa, I; Noguchi, S; Journal of Clinical Oncology 2016; Halnes, Geir; Mäki-Marttunen, Tuomo; Keller, Daniel; Kondo, A; Severin, J; Mungall, C; Arenillas, D; Mathelier, A; Volum 34.(21) s.2501-2508 Pettersen, Klas; Andreassen, Ole Andreas; Einevoll, Medvedeva, Y.A; Lennartsson, A; Drabløs, F; Ramilowski, Gaute. JA; Rackham, O; Gough, J; Andersson, R; Sandelin, A; Barfeld, Stefan; Mills, Ian Geoffrey. Engedal, Kim Nikolai; Seglen, Per O.. Effect of Ionic Diffusion on Extracellular Potentials in Lenasescu, H; Ono, H. Bono, Y. Hayashizaki, P. Carninci, Mapping Protein-DNA Interactions Using ChIP-exo and Autophagy of cytoplasmic bulk cargo does Neural Tissue. A.R.R. Forrest, T. Kasukawa* and H. Kawaji*. Illumina-Based Sequencing. not require LC3. PloS Computational Biology 2016 ;Volum 12.(11) Update of the FANTOM web resource: high resolution Methods in Molecular Biology 2016 ;Volum 1443. s.119-137 Autophagy 2016 ;Volum 12.(2) s.439-441 transcriptome of diverse cell types in mammals. Bauer, Johannes; Bakke, Oddmund; Morth, Jens Preben. Hong, Zebin; De Meulemeester, Laura; Jacobi, Annemarie; Nucleic Acids Research, 2016. doi: 10.1093/nar/gkw995

66 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 67 NCMM-AFFILIATED PUBLICATIONS NCMM-AFFILIATED PUBLICATIONS

Nucleic PRINT ISSN: 0305-1048 ONLINE ISSN: 1362-4962 K.; Staff, Anne Cathrine; Dybedal, Ingunn; Mills, Ian c-Myc Antagonises the Transcriptional Activity of the Acids

Research Nucleic Acids Geoffrey; Klungland, Arne; Staerk, Judith. Androgen Receptor in Prostate Cancer Affecting Key

VOLUME 44 ISSUE 22 2016 PAGES 10527–11033 Research Changes of 5-hydroxymethylcytosine distribution dur- Gene Networks. VOLUME 44 ISSUE 22 2016 https://academic.oup.com/nar ing myeloid and lymphoid differentiation of CD34+ cells. EBioMedicine. 2017 Epigenetics & Chromatin 2016;Volum 9.(1) Chellappa, Stalin; Hugenschmidt, Harald; Hagness, Tonby, Kristian; Wergeland, Ida; Lieske, Nora Valeska; Morten; Subramani, Saranya; Melum, Espen; Line, Pål Kvale, Dag; Tasken, Kjetil; Dyrhol-Riise, Anne Ma. Dag; Labori, Knut-Jørgen; Wiedswang, Gro; Tasken, Kjetil The COX- inhibitor indomethacin reduces Th1 effector & Aandahl, Einar Martin and T regulatory cells in vitro in Mycobacterium tuber- CD8+ T Cells That Coexpress RORγt and T-bet Are culosis infection. Functionally Impaired and Expand in Patients with Distal BMC Infectious Diseases 2016 ;Volum 16:599. s.1-12 Bile Duct Cancer. Journal of Immunology, 2017, 198 (4) 1729-1739

NARESE_44_22_Cover.indd 1 09/12/16 5:01 PM Vindedal, Gry Fluge; Thoren, Anna; Jensen, Vidar; McNair, C; Urbanucci, Alfonso; Comstock, CES; Augello, H, Kay J, Massie CE, Miller JL, Lamb AD, Ross-Adams H, Klungland, Arne; Zhang, Yong; Holtzman, Michael; Dukic, Aleksandra; Haugen, Linda Hofstad; Pidoux, MA; Goodwin, JF; Launchbury, R; Zhao, SG; Schiewer, MJ; Russell R, Nelson AW, Eldridge MD, Lynch AG, Ramos- Ottersen, Ole Petter; Nagelhus, Erlend Arnulf. Guillaume; Leithe, Edward; Bakke, Oddmund & Ertel, A; Karnes, J; Davicioni, E; Wang, L; Wang, Q; Mills, Montoya A, Mills IG, et al. Removal of aquaporin-4 from glial and ependymal mem- Tasken, Kjetil Ian Geoffrey; Feng, FY; Li, W; Carroll, JS; Knudsen, KE. The Early Effects of Rapid Androgen Deprivation on branes causes brain water accumulation. A protein kinase A-ezrin complex regulates connexin 43 Cell cycle-coupled expansion of AR activity promotes Human Prostate Cancer. European Urology. Molecular and Cellular Neuroscience 2016 gap junction communication in liver epithelial cells. cancer progression. 2016; 70(2):214-218. ;Volum 77. s.47-52 Cellular Signalling 2017; Volume 32 s 1- 11 Oncogene 2016 (36), 1655–1668; doi:10.1038/onc.2016.334 Shi, Jianxin; Hua, Xing; Zhu, Bin; Ravichandran, Wehbi, Vanessa Leila; Tasken, Kjetil. Geybels MS, McCloskey KD, Mills IG and Stanford JL. Munkley, Jennifer; Vodak, Daniel; Livermore, Karen Sarangan; Wang, Mingyi; Nguyen, Cu; Brodie, Seth Molecular mechanisms for cAMP-mediated immunoreg- Calcium Channel Blocker Use and Risk of Prostate Cancer E.; James, Katherine; Wilson, Brian T.; Knight, Bridget; A; Palleschi, Alessandro; Alloisio, Marco; Pariscenti, ulation in T cells - role of anchored protein kinase a sig- by TMPRSS2:ERG Gene Fusion Status. McCullagh, Paul; McGrath, John; Crundwell, Malcolm; Gianluca; Jones, Kristine; Zhou, Weiyin; Bouk, Aaron J; naling units. Prostate. 2017; 77(3):282-290. Harries, Lorna W.; Leung, Hing Y.; Robson, Craig N.; Mills, Boland, Joseph; Hicks, Belynda; Risch, Adam; Bennet, Frontiers in Immunology 2016 ;Volum 7:222. Ian Geoffrey; Rajan, Prabhakar; Elliott, David J.. Hunter; Luke, Brian T; Song, Lei; Duan, Jubao; Liu, Khan, A; Mathelier, A Glycosylation is an androgen-regulated process essential Pengyuan; Kohno, Takashi; Chen, Qingrong; Meerzaman, Intervene: a tool for intersection and visualization of for prostate cancer cell viability. DAoud; Marconett, Crystal; Laird-Offringa, Ite; Mills, Ian multiple gene or genomic region sets. EBioMedicine 2016 ;Volum 8. s.103-116 Geoffrey; Caporaso, Neil E; Gail, Mitchell H; Pesatori, bioRxiv, 2017. https://doi.org/10.1101/109728 Angela Cecilia; Consonni, Dario; Bertazzi, Pier Alberto; Munkley J, Mills IG and Elliott DJ. Chanock, Stephen J; Landi, Maria Theresa. Martin-Martin, R., Portantier, M., Chica-Balaguera, N., The role of glycans in the development and progression Somatic Genomics and Clinical Features of Lung Nyquist-Andersen, M., Mata, J., Lopez-Aviles, S. of prostate cancer. Adenocarcinoma: A Retrospective Study. A PP2A-B55-mediated crosstalk between TORC1 Nature Reviews Urology. 2016; 13(6):324-333. PLoS Medicine 2016 ;Volum 13 and TORC2 regulates the differentiation response in fission yeast. Rekvig, Ole Petter; Thiyagarajan, Dhivya; Pedersen, Hege Shi, Wenqiang; Fornes, Oriol; Mathelier, Anthony; Current Biology, 2017 Jan 23; 27(2):175-188) Lynum; Horvei, Kjersti Daae; Seredkina, Natalya. Wasserman, Wyeth W.. Future perspectives on pathogenesis of Lupus Nephritis: Evaluating the impact of single nucleotide variants on Massie CE, Mills IG and Lynch AG. facts, problems, and potential causal therapy modalities. transcription factor binding. The importance of DNA methylation in prostate American Journal of Pathology Nucleic Acids Research 2016 ;Volum 44.(21) s.10106-10116 cancer development. 2016 ;Volum 186.(11) s.2772-2782 Journal of Steroid Biochemistry Mol Biol. 2017; 166:1-15. Stiksrud, Birgitte; Lorvik, Kristina Berg; Kvale, Dag; Whitington, Thomas; Gao, Ping; Song, Wei; Ross-Adams, Ross-Adams, Helen; Ball, Stephen; Lawrenson, Kate; Mollnes, Tom Eirik; Ueland, Per Magne; Trøseid, Marius; Helen; Lamb, Alastair D.; Yang, Yuehong; Svezia, Ilaria; Ross-Adams H, Lamb AD, Dunning MJ, Halim S, Lindberg Halim, Silvia; Russell, Roslin; Wells, Claire; Strand, Siri H.; Tasken, Kjetil; Dyrhol- Riise, Anne Ma. Klevebring, Daniel; Mills, Ian Geoffrey; Karlsson, Robert; J, Massie CM, Egevad LA, Russell R, Ramos-Montoya A, Ørntoft, Torben F.; Larson, Melissa; Armasu, Sebastian; Plasma IP-10 is increased in immunological nonrespond- Halim, Silvia; Dunning, Mark J.; Egevad, Lars A.; Warren, Vowler SL, Sharma NL, Kay J, Whitaker H, Clark J, Hurst Massie, Charles E.; Asim, Mohammad; Mortensen, ers and associated with activated regulatory T cells and Anne Yvonne; Neal, David E.; Grönberg, Henrik; Lindberg, R, Gnanapragasam VJ, et al. Martin M.; Borre, Michael; Woodfine, Kathryn; Warren, persisting low CD4 counts. Johan; Wei, Gong-Hong; Wiklund, Fredrik. Corrigendum to “Integration of Copy Number and Anne Y.; Lamb, Alastair D.; Kay, Jonathan; Whitaker, Journal of Acquired Immune Deficiency Syndromes 2016 Gene regulatory mechanisms underpinning prostate Transcriptomics Provides Risk Stratification in Prostate Hayley; Ramos-Montoya, Antonio; Murrell, Adele; ;Volum 73.(2) s.138-148 cancer susceptibility. Cancer: A Discovery and Validation Cohort Study” Sørensen, Karina D.; Fridley, Brooke L.; Goode, Ellen L.; Nature Genetics 2016 ;Volum 48.(4) s.387-397 [EBioMedicine 2 (9) (2015) 1133-1144]. EBioMedicine. Gayther, Simon A.; Masters, John; Neal, David E; Mills, Subramani, Saranya; Perdreau-Dahl, Harmonie; Morth, 2017; 17:238 Ian Geoffrey. Jens Preben. HNF1B variants associate with promoter methylation The magnesium transporter A is activated by cardiolipin NCMM-AFFILIATED Zuber V, Bettella F, Witoelar A, Consortium P, Cruk G, and regulate gene networks activated in prostate and and is highly sensitive to free magnesium in vitro. PUBLICATIONS AT Q1 2017 Consortium B, Consortium T, Andreassen OA, Mills IG ovarian cancer. eLIFE 2016 ;Volum 5.(2016) and Urbanucci A. Bromodomain protein 4 discriminates OncoTarget 2016;Volum 7.(46) s.74734-74746 Barfeld SJ, Urbanucci A, Itkonen HM, Fazli L, Hicks JL, tissue-specific super-enhancers containing disease-spe- Tekpli, Xavier; Urbanucci, Alfonso; Hashim, Adnan; Thiede B, Rennie PS, Yegnasubramanian S, DeMarzo AM cific susceptibility loci in prostate and breast cancer. Shaw GL, Whitaker H, Corcoran M, Dunning MJ, Luxton Vågbø, Cathrine Broberg; Lyle, Robert; Kringen, Marianne and Mills IG. BMC Genomics. 2017; 18(1):270.

68 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 69 Selection of press items SELECTION OF PRESS ITEMS FROM NCMM 2016/Q1 2017 from NCMM 2016/Q1 2017 Selection of press items from NCMM 2016/Q1 2017

PRESS ITEMS FROM NCMM FOR 2016/Q1 2017 norinnetwork.no/blog/norin-congratulates-kjetil- task%C3%A9n-receiving-king-olav-v-price-cancer-re- 2016 search-2016 • UiO Faculty of Medicine News, March 2016: Bacteria use their own pumps to collect magnesium, research • NRK Radio P2, Ekko, March 10, 2016, Interview with from NCMM group leader Preben Morth featured: Anne Synnevåg about New data and development on http://www.med.uio.no/english/research/news-and- stress and cancer spread through the lymphatic sys- events/news/2016/bacteria-pumps-collect-magne- tem: https://radio.nrk.no/direkte/p2#start=10:04:42 sium.html • Dagbladet, 23 March 2016: En revolusjon i kreftbehand- • Science Daily, April 2016: Bacteria use their own lingen: http://redir.opoint.com/?key=7ABntAryxnmi pumps to collect magnesium: https://www.science- nBHcOx8M daily.com/releases/2016/04/160406100529.htm VG, 31 May 2016: «Pille til 80 øre kan redde 1 av 5 NCMM Director, Professor Kjetil Taskén, awarded King tarmkreftpasienter»: Olav V’s Prize for Cancer Research 2016 http://www.vg.no/nyheter/innenriks/helse-og-medisin/ 1. The Norwegian Cancer Society, 9 March 2016: pille-til-80-oere-kan-redde-1-av-5-tarmkreftpasien- Kong Olavs kreftforskningspris 2016: https:// ter/a/23698641/ kreftforeningen.no/aktuelt/siste-nyheter/ kong-olav-vs-kreftforskningspris-2016/ June 2016: Kveldsnytt – Interview with Kjetil Taskén 2. UiO Faculty of Medicine, March 9, 2016: Kjetil about paper in Journal of Clinical Oncology Taskén får Kong Olav Vs kreftforskningspris: http:// www.med.uio.no/om/aktuelt/aktuelle-saker/2016/ United Press International (UPI), 2 June 2016, Low dose of kjetil-tasken-kreftforskningsprisen.html aspirin tied to longer colon cancer survival: http://www. 3. Oslo Cancer Cluster, March 9, 2016: Kjetil Taskén upi.com/Health_News/2016/06/02/Low-dose-aspirin- awarded King Olav V’s Cancer Research Award 2016 tied-to-longer-colon-cancer-survival/6511464896717/ - http://occincubator.com/professor-kjetil-tasken-at- the-university-of-oslo-awarded-king-olav-vs-cancer- 6 June 2016: Presentation of the King Olav V’s Prize research-award-2016/ for Cancer Research: 4. Forskning.no, March 9, 2016: Kongelig pris til kreftfor- 1. Included on TV2 News sker i Oslo: 2. Konghuset: http://forskning.no/kreft-forskningspriser/2016/03/ http://www.kongehuset.no/nyhet.html?tid=136269 kongelig-pris-til-kreftforsker-i-oslo &sek=26939 2017 2017/03/06/Per-Ottar-Segel-f%C3%A5r-Kong-Olav-Vs- 5. OsloBy, March 9, 2016, Kongelig pris til kreftforsker: 3. Budstikka: http://www.budstikka.no/kreft/kjetil-task • Titan.uio.no, 9 February 2017: Leter etter snarvei i den kreftforskingspris-14399587.ece http://www.osloby.no/nyheter/Kongelig-pris-til- -n/jar/kjetil-task-n-mottok-prestisjetung-pris-for-kreft- individtilpassede kreftbehandlingen: https://titan.uio.no/ 4. Oslo University Hospital, King Olav V’s Prize kreftforsker-8387376.html forskning/s/5-55-324452 node/2146 for Cancer Research: http://www.ous-research.no/home/ 6. Aftenposten, 10 March 2016, Kongelig pris til kreftfor- 4. Kreftforeningen, Kreft forskning pris vinner: https:// • Dagens Medisin, 16 February 2017: Kan føre til at institute/news/17011 sker (page 6) kreftforeningen.no/aktuelt/siste-nyheter/kreftfors- vi må omdefi nere evidensbasert medisin (Feature on 5. Budstikka, 13 March, Bærumsforsker får kreftfors- 7. KG Jebsen Centre for Cancer Immunotherapy, March kningsprisvinner-med-oppsiktsvekkende-studie/ presentation given by Kjetil Taskén at Oslo Life Science kningspris: https://www.budstikka.no/kreftforeningen/ 10, 2016, Kjetil Taskén Receives King Olav V’s Prize: 5. Kong Olavs Kreftforskningsprisen 2016: https://kreft- Conference): https://www.dagensmedisin.no/artikler/ kreft/forskning/barumsforsker-far-kreftforsknings- http://www.med.uio.no/klinmed/english/research/ foreningen.no/forskning/kong-olav-vs- 2017/02/16/-kan-fore-til-at-vi-ma-omdefi nere-evidens- pris/s/5-55-450691 centres/kgj-cancer-immunotherapy/news-and- kreftforskningspris/kreftforskningsprisen-2016/ basert-medisin/ 6. Titan.uio.no, 16 March, Kong Olav Vs kreftforsknings- events/news/2016/jcit-scientist-kjetil-taskén-recie- pris til Per Ottar Seglen: https://titan.uio.no/node/2222 ves-king-olav-vs.html • NRK radio interview with Kjetil Taskén, in connec- Professor Per Seglen awarded King Olav V’s Prize for 8. Oslo University Hospital research pages, March 2016: tion with a specialist meeting about immunotherapy in Cancer Research Publication of NCMM co-authored report into digital King Olav V’s Cancer Research Prize for 2016 to Kjetil Hamar, 28 September 2016 (NRK Hedmark og Oppland) 1. Dagens Medisin, 6 March 2017, UiO professor hedres biotechnology in Norway Taskén: • Oppslag i Oppland Arbeiderblad, 28 September 2016, med prestisjes pris for kreftforskning: https://www. 1. Titan.uio.no, 21 March, Digital bioteknologi = raskere http://www.ous-research.no/home/ous/news/15957 news about Kjetil Tasken and meeting about immunothe- dagensmedisin.no/artikler/2017/03/06/uio-professor-he- utvikling + lavere pris: https://titan.uio.no/node/2241 9. UiO, Faculty of Science and Mathematics, March rapy in Hamar. dres-med-prestisjepris-for-kreftforskning/ 2. Dagens Medisin, 22. March 2017, Digitalisering gir 11, 2016, Kong Olav V’s kreftforskningspris til Kjetil • Budstikka: Asker og Bærums Budstikke, 29 October 2. Kreftforeningen, 6 March 2017, Kong Olav Vs kreft- færre utfordringer med innovasjon: https://www.dagens- Taskén: https://titan.uio.no/node/1404 2016, Ni kreftforskere får 53 mill: – Vi er takknemlige: http:// forskningspris: https://kreftforeningen.no/aktuelt/siste- medisin.no/artikler/2017/03/22/digitalt-orienterte-bio- 10. Norwegian Infl ammation Network, NORIN, March 11, www.budstikka.no/institutt-for-kreftforskning/kreft- nyheter/kong-olav-vs-kreftforskningspris-2017/ teknologibedrifter-har-farre-innovasjonsutfordringer/ 2016, NORIN congratulates Kjetil Taskén on receiv- studie/forskning/ni-kreftforskere-far-53-mill-vi-er-takk- 3. Fordbladet, 6 March 2017, Kong Olav Vs kreftfors- ing King Olav V Prize for Cancer Research: http:// nemlige/s/5-55-388830 kningspris: http://www.fjordabladet.no/npk/innenriks/

70 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 71 Core Facilities at NCMM NCMM hosts several core facilities that are all open for use by researchers from outside the Centre. Core facilities at NCMM include:

HIGH-THROUGHPUT ZEBRAFISH PEPTIDE ARRAY CHEMICAL BIOLOGY CORE FACILITY CORE FACILITY SCREENING PLATFORM NCMM has both tanks for keeping Equipment is available for: Services offered at NCMM The platform supports the discovery • Liquid Handling Informatics zebrafi sh, and separate tanks for • Microinjection • Synthesis of peptide arrays on of small molecules to probe, explore — Hamilton Microlab Star With the facility’s dotmatics data- generating/regenerating fi sh lines. • Behavioural tracking and cellulose membranes and modulate biological systems. — Echo 550 connected to a fully base system the CB Platform can The facility also has tanks for chemical screening: • Synthesis of lyophilized peptides automated workstation provide results in our standard breeding, three iSPAWN for large • Larvae manipulation and imaging • Amino acid analysis of peptide Services (Labcyte Access) format or one customised for your scale production of synchronized • To come: EEG hydrolysates • High-throughput screening of — BioTek MultiFlo FX dispenser/ own set-up. Even if you don’t have eggs, and nets. small molecules. Projects can washer your own database, one can be The facility’s personnel have experi- Contact: use our in-house libraries (total — Thermo Fisher Scientifi c provided to you with remote access ence within aqua culture, fi sh health, Ola Rumohr Blingsmo, of 68,000 compounds) or those Cytomat Cell Incubator to the Dotmatics server allowing screening and characterisation of Senior Engineer supplied by the customers — Brooks FluidX® XPeel® you to query and analyse your own new lines, GMO, 360° live-imaging themselves Automated Microplate DeSealer results. of larvae, chemical screening, behav- Check the NCMM Core Facilities web • Assay development assistance ioural tracking, and microinjection pages for more detailed information • Data management Other Instrumentation For fi le transfer, encrypted VPN (automatic/manual). about our core facilities. • PerkinElmer FlexDrop access is provided to the facility’s Technologies Exi dispenser secure server. Users can use the facility to do their • Detection Platforms • Agilent PlateLoc Thermal research, or they can buy services — PerkinElmer EnVision® Microplate Sealer Contact persons: Key personnel at the core facilities. and analyses. Multilabel Plate Reader • BenchCel Microplate Handling Johannes Landskron From left: Daniel James Wrobleski, Eirin — Molecular Devices FLIPR384 Workstation (Platform manager) Solberg, Ola Rumohr Blingsmo, Johannes Contact: Fluorometric Imaging • Eppendorf microtitre and Paul Ragnar Berg Landskron, Paul Ragnar Berg, and Rønnaug Steen Kolve, Plate Reader plate centrifuge (Head Engineer) Rønnaug Steen Kolve. Head Engineer — BD LSR Fortessa HTS • Barcode printing and reading fl ow cytometer • Biotek EL406 plate washer and — BioTek Synergy™ Neo2 Multi- dispenser workstation Mode Microplate Reader • Roylan StoragePod — IntelliCyt iQue Screener PLUS

72 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 73 Personnel PERSONNEL AT NCMM Ellen Østensen MSc Students PhD Fellows STRUCTURAL BIOLOGY at NCMM Marthe Jøntvedt Jørgensen Julia-Kristina Madsen-Østerbye AND CHROMATIN Johanne Hermansen Uthus Oksana Svärd NCMM Group Leader Administrative Officer Nikolina Sekulic Berit Barkley COMPUTATIONAL BIOLOGY DIRECTOR AND (Core Facility Leader) (from June 2016) AND GENE REGULATION Principal Engineer ADMINISTRATION Rønnaug Kolve Steen PhD Fellows Stine Malene Hansen Wøien (Head Engineer) Saranya Subramani (until May 2016) BREAST CANCER NCMM Group Leader Director Theis Sommer (until June 2016) GROUP Anthony Mathelier (from May 2016) Senior Researcher Kjetil Taskén Senior Engineers Julia Weikum (from April 2017) Dario Segura-Pena Eshrat Babaie NCMM Group Leader Postdoctoral Fellow Chief Administrative Officer Gladys Tjørhom MSc Student Antoni Hurtado Aziz Khan (from October 2016) Ingrid Kjelsvik (on leave) Stefanie Ruhland (Erasmus Student, BIONANOTECHNOLOGY April 2016 – July 2016 Head Engineer PhD Fellow AND MEMBRANE SYSTEMS Acting Chief Administrative Officer/ RESEARCH GROUPS: Annika Kratzel (Erasmus Student, Siv Gilfillan Marius Gheorghe (from September Head of Office PROSTATE CANCER GROUP April 2017 - July 2017) 2016) NCMM Group Leader Elisa Bjørgo Postdoctoral Fellows Irep Gözen (from September 2016) NCMM Group Leader Anne Marthe Fosdahl MSc Student Acting Deputy Head of Office Ian Mills (until June 2016) SIGNALLING NETWORKS IN (from September 2016) Eleftherios Pavlos (Erasmus student, Siri Høgseth HEALTH AND DISEASE Venkata S. Somisetty October 2016- March 2017) Head Engineers (until January 2017) Financial Officers Ingrid Jenny Guldvik NCMM Group Leader Sachin Kumar Singh Mette Kvernland (until June 2016) Kjetil Taskén CELL CYCLE REGULATIONS Anita Skolem Frank Sætre (until July 2016) PhD Fellow Scientific Officers Elisa Fiorito NCMM Group Leader Human Resources Officer Senior Researcher Marianne Enger (until May 2016) Sandra Lopez-Aviles Nina Modahl Nikolai H. Engedal Martine Schrøder Shixiong Wang Head Engineer Communications Officer Guest Researcher Senior Researchers MSc Student Mari Nyquist-Andersen Annabel Darby (from January 2017) Per O. Seglen Einar Martin Aandahl Neus Daviu Postdoctoral Fellows (Erasmus student, Nathalia Chica-Balaguera THE ADMINISTRATION Higher Executive Officer Postdoctoral Fellows Postdoctoral Fellows September 2016 - April 2017) Ruth Martîn Martîn TEAM AT NCMM Carlos Romeo Rodriguez Harri Itkonen Theresa Ahrens Marina Portantier Alfonso Urbanucci (from July 2016, joint with Assistant NCMM benefits from the support of IT Team Staerk group) Signe H. Kaarstad a full administrative team that pro- George Magklaras (Head of IT) PhD Fellows Simer Jit Bains (NCMM affiliate) (until February 2017) CHEMICAL vides service to the Centre’s research Gang Cheng Lisa Gerner (until February 2017) Deepak Balaji Thimiri Govinda Raj NEUROSCIENCE groups. Melaku Tadesse Morten Luhr Ana I. Costa Calejo Bertrand Simon - Joint PhD student Stalin Chelappa (from July 2016) STEM CELL GROUP NCMM Group Leader The team is led by acting CAO, Elisa LABORATORY OPERATIONS at EMBL Hamburg Dinh-Toi Chu Camila Vicencio Esguerra Bjørgo. All administrative and sup- AND CORE FACILITIES (until March 2017) Andrea Cremaschi NCMM Group Leader port functions, including labora- Paula Szalai (from October 2016) Judith Staerk Head Engineer tory operations and core facilities, HSE Coordinator Aleksandra Dukic Rønnaug Steen Kolve finance, HR, research administration, Liv E. Alver Bjørland (from January 2017) Principal Engineer IT, and communications are carried MEMBRANE TRANSPORT Kushi Kushekar Kirsti E. Præsteng Postdoctoral Fellows out in-house by the Centre’s dedi- Chemical Biology Platform GROUP Anna-Mari Lone David Ramonet-Jimenez (from cated administration department. Johannes Landskron Kristina B. Lorvik Postdoctoral Fellows September 2016) (Platform Manager) NCMM Group Leader Maria-Niki Mylonakou Theresa Ahrens Ettore Tiraboschi With the merging of NCMM and Paul Ragnar Berg (Head Engineer) Jens Preben Morth (until May 2016) (from July 2016, joint with BiO, administration-related staff Eirin Solberg (Principal Engineer) Principal Engineer Vanessa L Wehbi (until January 2017) Taskén Group) Research Technician now number 18 full-time employees; Bojana Sredic PhD Fellows Safak Caglayan Daniel James Wrobleski including engineers working at our Peptide Synthesis Service Simer Jit Bains (until January 2016) Artur Cieslar-Pobuda core facilities. Ola Rumohr Blingsmo Postdoctoral Fellows Stalin Chelappa (until June 2016) Adnan Hashim MSc Students Johannes Bauer Aleksandra Dukic (until December Ida Jonson Gezime Seferi (from February 2017) Zebrafish Core Facility Harmonie Perdreau-Dahl 2016) (until October 2016) Anna Thao Nguyen Camila V. Esguerra Saranya Subramani Nora V. Lieske (until June 2016) Marie Rogne (from August 2016)

74 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 75 NCMM International PersonnelNCMM ASSOCIATE INVESTIGATORS statistics AND YOUNG ASSOCIATE INVESTIGATORS staff distribution

Number of employees

FINLAND 100 2%

POLAND 2% 80 DENMARK 5% GERMANY CHINA 15% 3% ROMANIA 60 2% PAKISTAN IRAN UK UKRAINE 3% UK 2% 3%1% 2% FRANCE CROATIA 40 5% 2%

USA 5% 20

TURKEY VIETNAM NCMM Staff (incl. FP) PORTUGAL 3% INDIA EL SALVADOR ETIOPIA 3% 2% 3% 2% 10% NCMM Staff (excl. FP) GREECE 0 COLOMBIA 5% 2% SPAIN 2010 2011 2012 2013 2014 2015 2016 2017 8% SERBIA ITALY The staff was reduced in 2015 and 2016 due to rotation of two Numbers for 2017 are estimated and represents the Centre after 3% research groups out of the centre. In addition, the Founding the merger. The newly merged NCMM has in total 3 research 7% Partner (FP) arrangement was terminated in 2015. In 2016, one groups recruited in 2016. In addition, the Centre is planning to KOSOVO new research group rotated in and this group will grow in size in recruit two more groups in 2017/2018. We therefore expect to see 2% the coming years. Furthermore, a second group leader/assistant an increase in staff the next couple of years. director has recently been recruited and will start in the fall 2017.

ARGENTINA 2% All Staff Group leaders 1% Director 4% 10% 8% Group leaders 3% 6% Senior researchers Director Postdocs 8% Group Leaders NCMM Type of SeniorPhD Researchers fellows Gender Gender Female 63% international 37% employment6361%%63% Postdocs3739%%37% 6156% 61% Balance 3944% 39% 56% 56% Balance 44% 44% Male staff PhD Engineersfellows EngineersAdministration 17% 30% Norway Administration IT IT International Students Students 13% Other personell Other personell

The overview represents the merged NCMM in the beginning of 2017.

76 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 CENTRE FOR MOLECULAR MEDICINE NORWAY | ANNUAL REPORT 2016 77

Grafi Foto: sk Ottesen design:Trykk: Millimeterpress Rolf

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NCMM CO-FUNDERS

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INTERNATIONAL COLLABORATIONS INCLUDE