Annual Report 2016
From disease mechanisms to clinical practice
NORDIC EMBL
PARTNERSHIP FOR
Overview from the Director NCMM History in Brief
Merger between NCMM and BiO Welcome to the new Assistant Director
NCMM Research NCMM Group Leaders
Group Taskén – Signalling Networks in Health and Disease Group Mills – Prostate Cancer
Group Morth – Membrane Transport Group Hurtado – Breast Cancer Group Staerk – Stem Cells
Group Mathelier - Computational Biology and Gene Regulation Group Lopez-Aviles - Cell Cycle Regulations
Group Esguerra – Chemical Neuroscience
Group Sekulic – Structural Biology and Chromatin
Group Gözen – Bionanotechnology and Membrane Systems
NCMM Associate Investigators Research Collaborations
From Disease Mechanisms to Clinical Practice Research Highlights
News and Events 2016 King Olav V Prize 2016 Network Meeting 2017 NCMM PhD Dissertations NCMM Board
Scientific Advisory Board NCMM Funding
NCMM-affiliated Publications and Press items Core Facilities
Personnel
4 66 7
88 1014 1822 2630 3438 4044
48 50 52 53 5657 60 61 62 64 65 66 72 74
NCMM extramural funding, in the form of grants to 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 grants. This slight decrease in comparison to previous years is due to some research groups rotating out of the Centre.
How has the Nordic EMBL Partnership benefi ted NCMM in terms of research collaborations, networking, and infrastructure?
NCMM has been able to enjoy collaborations across the Nordic EMBL Network with all three other nodes, and there has also been a lot of collaboration between NCMM’s own research groups. Speakers from each Nordic EMBL Partnership node have been invited for visits at other nodes, and these visits and networking are something we hope to see more of in the future.
We have also been able to make great use of the var- ious outstanding infrastructures offered across the nodes, such as Chemical Biology infrastructures. A separate NordForsk grant has also further helped to facilitate more Chemical Biology collaboration across the nodes.
What are you most looking forward to in the year ahead?
NCMM has a great set of research groups and a lot of very talented staff. I look forward to seeing NCMM groups and individual researchers that have been working hard towards well-defi ned and ambitious goals for extended periods of time capitalise on all their research efforts.
I also look forward to seeing how the most recently recruited groups develop, and what directions they take.
Lastly, I look forward also to upcoming recruitments of even newer groups to set up new research in NCMM. It is always an exciting time in a place like NCMM.
In a more general context, I am looking forward to the Helsinki NMMN meeting in September, the next NCMM national network meeting in January 2018, and what ambitious goals we can reach for jointly at the Nordic level.
Professor Kjetil Taskén, NCMM Director NCMM Director, Professor Kjetil Taskén, answers some
questions on the highlights and developments at NCMM during 2016/Q1 2017:
What were your highlights of 2016?
2016 and early 2017 was a busy, but very successful time for NCMM. In our seventh year, NCMM has grown and further built on its successes to become an even more established and important presence in the European molecular research world.
For me, as Director, some highlights from 2016 and Q1 2017 were:
1. The merger of NCMM and the Biotechnology Centre.
This was fi rst initiated in 2016, and came fully into effect at the start of 2017. The merger gives us a more robust centre, with larger scientifi c mass, and also a good basis with infrastructure and technology plat- forms, as well as an even stronger international net- work. NCMM will be home to 11 research groups and technology platforms across two branches; NCMM Translational Research and NCMM Biotechnology, known collectively as NCMM
2. Securing the funding of NOR-OPENSCREEN as a national infrastructure for chemical biology. Funding of 33 mNOK, headed by UiO (NCMM), and with University of Tromsø (UiT), SINTEF, and University of Bergen (UiB) as partners from 2016; and to join EU-OPENSCREEN as a founding member when it is established in 2017 3. Norway entering EATRIS as a full member from 2016,
headed by NCMM and with UiO, UiB, NTNU, UiT, and all four Regional Health Authorities of Norway;
Northern, Southern and Eastern, Western, and Central, as partners. This was approved by the Research Council of Norway and the Department of Health and Social Services
4. A very successful EMBL Partnership meeting in June 2016 in Heidelberg
5. The fi rst NCMM Network Meetings in January 2016, and a second Network meeting in February 2017.
NCMM has also added to its research expertise and talent base, by appointing three new Group Leaders, Anthony Mathelier, Nikolina Sekulic, and Irep Gözen. I greatly look forward to seeing these three new groups grow and develop over the coming years.
Furthermore, NCMM has appointed an Assistant Director,
Hartmut Luecke, a structural biologist. He is currently based at University of California, Irvine, where he is the director of the university’s Centre for Biomembrane Systems and a Professor of Biochemistry. Professor Luecke will offi cially join NCMM in November 2017.
It was also a really successful year for NCMM in terms of outputs, widening and strengthening our collabora- tions, and growth and consolidation of external fund- ing. NCMM Group Leaders report 60-plus national col- laborations, which just goes to show the strength and breadth of molecular research taking place at NCMM, and the importance and relevance of this research on a national level.
Our Group Leaders are also increasingly collaborating with researchers all over the globe; this year 50-plus international collaborations have been reported.
What do you see as the main areas of progress and success for the Nordic EMBL Partnership?
The Nordic EMBL Partnership is working very effectively;
the four centres continue to develop, and the attendance at our annual gatherings and our many other interactions continue to increase. MIMS is now, as the fi rst of the four centres, starting its 3rd fi ve-year funding period, while DANDRITE has been evaluated in its fi rst fi ve-year period, with extension approved by the Board for a further fi ve years. The support from NordForsk also ties the four centres together with joint travel grants, courses, and exploitation of infrastructures across the four centres.
Future areas of progress will include more shared posi- tions, and thus more collaboration and shared projects;
if we are able to launch funding for this as planned.
Furthermore, the Partnership has formulated new joint interest areas as a basis for grand challenge projects across two or more centres.
How have translational research studies progressed at NCMM over the last year?
NCMM PIs reported around 50 NCMM-affi liated publica- tions in 2016, and the fi rst quarter of 2017. This includes papers published in Nature Genetics, Oncogene, Current Biology, Journal of Clinical Oncology and many more.
Furthermore, there are around 27 clinical trial projects either ongoing or underway, showing that the breadth and depth of research at our centre is continuing to develop and expand.
An overview
from the Director
2016 saw a number of important developments for NCMM, including the merger with the Biotechnology Centre, and the appointment of three new Group Leaders.
Professor Kjetil Taskén, NCMM Director
AN OVERVIEW FROM THE DIRECTOR
MERGER BETWEEN NCMM AND BIO
The merger between Centre for Molecular Medicine Norway (NCMM) and the Biotechnology Centre of Oslo (BiO) formally came into effect on 2 January 2017.
The new NCMM consists of two departments: NCMM Translational Research (the former NCMM) and NCMM Biotechnology (former BiO). The centre now comprises of 11 Research Groups.
Prior to the merger, NCMM and BiO were parallel Centres with a shared model. Both recruited young group leaders to 5+4 year non-tenured positions, and operated with a joint Director.
Following letters from the European Molecular Biology Laboratory (EMBL), The South-Eastern Norway Regional Health Authority (Helse Sør-Øst), and the Research Council of Norway supporting a merger, the Board of the Faculty of Medicine, on behalf of University of Oslo, decided in June 2016 that BiO and NCMM would merge.
The merger of BiO and NCMM will serve to significantly strengthen the Centre scientifically and strategically, alongside reinforcing local anchoring, funding base, and infrastructure. The Centre is still located at Oslo Science Park.
WELCOME TO NEW NCMM ASSISTANT DIRECTOR, HARTMUT LUECKE
NCMM is delighted to welcome Professor Hartmut Luecke as the Centre’s new Assistant Director.
Professor Luecke is a structural biologist currently based at the University of California, Irvine, where he is Director of the Centre for Biomembrane Systems and a Professor of Biochemistry.
Professor Luecke’s research interests include crystal- lographic and cryo-EM studies of membrane proteins, with work spanning from discovering how Helicobacter
proteins, RNA editing, p53, drug discovery, and chemi- cal biology. He will therefore be an excellent addition to the structural biology community in Oslo.
Professor Luecke studied for his B.S. at Heidelberg University in Tiffin, Ohio, before obtaining his Ph.D. at Rice University in Houston, Texas.
Professor Luecke is expected to start working with NCMM in November 2017, with a full presence at the centre from January 2018.
2001-2004 2005-2007 2008 2009 2010* 2011 2012* 2013* 2014* 2015* 2016* 2017
* PhD course in molecular medicine
Taskén appointed Interim Director (2009-2010)
EATRIS
3 Group Leaders hired:
Nagelhus, Mills and Morth
Appointment of 7 Associate Investigators
Taskén appointed Director (2011-2015) EU-OPENSCREEN
1 Group Leader hired: Hurtado
Appointment of 5 Associate Investigators
1 Group Leader hired: Staerk
4th NMMN Meeting in Oslo
First Group, Nagelhus, rotates out
5 new Associate Investigators and 7 new Young Associate Investigators appointed
Taskén re-appointed Director (2016-2020)
Second Group, Mills, rotates out
2 new Group Leaders, Gözen and Sekulic, hired to BiO
Hartmut Luecke appointed Assistant Director (2017-2021)
Planning &
Approval process
Financing discussions
& negotiations
Nordic EMBL Partnership Agreement
NCMM formally established
Recruitment of first group leaders
NCMM Board appointed
Start of operations
SAB established
First NCMM publications Official
inauguration
1st operational year
1st SAB visit 2nd SAB visit
Renewal & Expansion of the Nordic EMBL Partnership Agreement (2013-2023)
NCMM 5-year Evaluation
Funding for 2nd period (2015-19) secured 3rd SAB visit
NCMM Board re- appointed 4th SAB visit
NCMM organised under UiO Faculty of Medicine
Merger decision NCMM and BiO 5th SAB visit
Norway becomes official member of EATRIS-ERIC, Funding of NOR- OPENSCREEN as national Norwegian infrastructure
Merger between BiO and NCMM completed, taking total number of research groups to 11 1 Group Leader hired:
Mathelier
New Group Leader Esguerra hired to BiO
Network Meeting in Oslo
Rotation of SAB Chair out, new SAB member appointed
SAB re-appointment BiO
• BiO was established in 1989
• After evaluation by UiO in 2002, BiO was reorganised under the EMBL model
• In 2003, Kjetil Taskén was appointed as a new Centre Director
• Following the reorganisation, BiO was set up as a centre for molecular biology, biotechnology and bioinformatics
• The centre had six internationally-recruited research groups, in addition to core facilities.
RESEARCH GROUPS RESEARCH GROUPS
a Group Leader at NCMM in 2011 and his research is focused on breast cancer, estrogen sensitivity, and the role of co-factors in transcriptional networks.
Dr. Judith Staerk trained at the Ludwig Institute for Cancer Research and Catholic University in Brussels, did her postdoc at Whitehead Institute, MIT, Boston, US working with stem cells and started in her NCMM Group Leader appointment in 2012. Her research is focused on stem cell biology, hematopoietic stem cells and myelodysplastic and myeloproliferative syndromes.
Staerk’s appointment as group leader was evaluated in the autumn of 2016 and her position was renewed for a second fi ve-year period (2017-2022).
Dr. Anthony Mathelier is a computer scientist by back- ground who did his PhD at the Pierre and Marie Curie University, Paris. Mathelier was recruited from the University of British Columbia, Vancouver, Canada, which is where he also did his postdoc. Mathelier started his NCMM Group Leader appointment in May 2016. His computational biology research programme focuses on gene expression regulation and the mecha- nisms by which it can be disrupted in human diseases such as cancer.
NCMM Biotechnology
Dr. Sandra Lopez-Aviles did her PhD in Barcelona fol- lowed 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 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.
Dr. Nikolina Sekulic did her PhD at the University of Illinois in Chicago, followed by a postdoc in the lab- oratory of Professor Ben Black at the University of Pennsylvania, Philadelphia. She started as Group Leader at BiO in January 2016 and her research is focussed on structural biology and epigenetics.
Dr. Irep Gözen did her PhD in chemical and biological engineering at Chalmers University of Technology in Gothenburg, Sweden followed by a postdoc at Harvard- MIT Health Sciences and Technology. She started her group leader appointment at BiO in September 2016 and her research programme will focus on the development and utilization of bionanotechnology-based methods.
NCMM has recently also recruited a new senior group leader/assistant director. Professor Hartmut Luecke is a structural biologist, currently based at the University of California (UC), Irvine and will join NCMM in November 2017.
Furthermore, NCMM will start the process of recruiting two new group leaders in autumn 2017. The research groups at NCMM are presented in more detail in the fol- lowing pages.
THE CURRENT GROUP LEADERS AT NCMM/BIO INCLUDE:
NCMM Translational Medicine
Professor Kjetil Taskén, identifi ed by the Research Council as one the founding members of NCMM, served as Interim Director 2008-10. Professor Taskén was appointed Director from January 2011 and reappointed for a second 5-year period from 2016. His research is in the area of cell signal- ling and immunomodulation, with application in immune diseases, infl ammation, and tumour immunology.
Dr. Ian G. Mills was recruited from Cambridge Research Institute, Cancer Research UK, University of Cambridge in 2010. Mills is interested in transcriptional and regulatory networks in prostate cancer and aims to better defi ne the interplay between membrane traffi cking, metabolism, and transcription in prostate cancer, as proteins in reg- ulatory hubs for these processes have potential value as
cancer biomarkers and therapeutic targets. Mills accepted a position at Queens University of Belfast in 2015 and rotated out of NCMM in June 2016.
Dr. Jens Preben Morth was trained in structural biology at the EMBL Outstation in Hamburg and was recruited from Aarhus University to NCMM in October 2010. His research is in the area of structure and function of mem- brane transporters. Morth has also started a new pro- gramme on pH regulation and structure function studies on bicarbonate transporters. His research has relevance to cardiology, neurobiology, and kidney diseases. Morth’s appointment as group leader was evaluated in 2015 and his position was renewed for a second fi ve-year period (2015-2020).
Dr. Toni Hurtado did his PhD at the Vall Hebron Hospital in Barcelona and his postdoc at Cambridge Research Institute, University of Cambridge. Hurtado started as
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 Group Leaders
NCMM GROUP LEADERS
Group Leaders at NCMM should be young, outstanding researchers in an
international context. Each has been recruited to non-tenured 5+4 year positions,
with a start-up package to set up a research group. These positions are research
scientist positions at a level comparable with Associate or Full Professor.
A main focus of the Taskén Group is to understand why the immune system sometimes turns off its ability to rec- ognise and kill cells in an expanding malignant tumour.
We aim to understand how tumours develop immune evasion strategies, what mechanisms operate in differ- ent cancers, and how we can perturb such immune-in- hibitory signals to boost anti-tumour immunity and assist other cancer immunotherapies.
We are starting work with cancer drug sensitivity screening on patient samples, looking for efficacious compounds and drug synergies on an individual basis, ultimately aiming to assist clinical decisions in preci- sion oncology and haematology. Other activities focus on the role of the cAMP second messenger system and other signal networks in the regulation of cellular function and its involvement in disease mechanisms in inflammation as well as in infectious, metabolic and cardiovascular diseases.
DESCRIPTION OF THE GROUP’S RESEARCH
The group aims to understand complex intracellular signalling networks and how such networks require anchoring and localisation through A kinase anchoring proteins (AKAPs) or other scaffold proteins. The group investigates how these signalling networks mediate hor- monally regulated physiological and pathophysiological processes. In the immune system we investigate cAMP- and regulatory T cell-mediated immune-modulation with application in immune diseases, inflammation and tumour immunology. In pursuit of this understanding the group maps signalling pathways, identifies targets, devel- ops tools to perturb signalling (peptidomimetics, small
molecular compounds) and provides “proof-of-principle”
experiments using specific disease models.
The Taskén group employs a breadth of techniques in bioinformatics, proteomics, phospho-flow analysis, chemical biology high-throughput screening assays and genetic tools in order to screen new targets for in vitro and in vivo function. In order to isolate signalling com- plexes from a variety of targets, including T cells, cardio- myocytes, adipocytes, and organelles such as lipid drop- lets and mitochondria, a chemical genomics approach is used in combination with phospho-proteomics to understand spatiotemporal dynamics of phosphoryla- tion in anchored signalling complexes. Chemical biology screenings identify small molecular compounds for our research. Furthermore, phospho-flow cytometry using fluorescent cell barcoding allows mapping of complex signal networks, assessing how inhibitory signals feed in and examining how small molecules perturb such sig- nal networks. Our recent technology developments now also allow flow-based signalling analyses of adherent cells and high-throughput chemical biology screening by flow cytometry.
The group studies cAMP immunomodulation and involvement of regulatory T cells in HIV, mouse AIDS, and various cancers where tumour immunology is of significance. Projects include studies of regulatory T cells and anti-tumour immune responses in colorectal cancer, pancreatic cancer, cholangiocarcinoma and ovarian carcinoma. In addition, cancer and immune cell sig- nalling analyses are being performed by phospho-flow cytometry to find bio signatures. A recent interest is now to rig drug sensitivity screens to explore the pos- sibility to assist treatment choices in individualised
Kjetil Taskén
Signalling Networks
in Health and Disease
RESEARCH GROUPS: KJETIL TASKÉN RESEARCH GROUPS: KJETIL TASKÉN
GROUP MEMBERS
Research Scientists Einar Martin Aandahl Johannes Landskron Sigrid Skånland Postdoctoral FellowsTheresa Ahrens (joint with Staerk group) Simer Jit Bains (NCMM, affiliate)
Deepak Balaji Thimiri Govinda Raj Ana I. Costa Calejo
Stalin Chelappa (from July 2016) Dinh-Toi Chu
Andrea Cremaschi (from October 2016) Aleksandra Dukic (from January 2017) Kushi Kushekhar
Anna-Mari Lone Kristina B. Lorvik
Vanessa L Wehbi (until January 2017) Nn, open postdoc
(Cancer Society grant, 2017- hiring ongoing) Nn, open postdoc
(Helse Sør-Øst grant, 2017- hiring ongoing) Nn, open postdoc
(KG Jebsen Centre grant, 2017- hiring ongoing) PhD. Fellows
Stalin Chelappa (until June 2016)
Aleksandra Dukic (until December 2016) Nora V. Lieske (until June 2016)
Ellen Østensen MSc/MD Students
Johanne Hermansen Uthus Marthe Jøntvedt Jørgensen Administrative Officer Berit Barkley
Scientific Officers Marianne Enger Martine Schrøder Gladys Tjørhom
COLLABORATIONS
International collaborationsWe currently collaborate with the groups of Professor John D. Scott, University of Washington, Seattle; Professor Friedrich Herberg, Universität Kassel;
Professor Sven Enerbäck, Göteborgs Universitet;
Professor Manuela Zaccolo, University of Oxford;
Dr. Enno Klussmann, Max Delbrück Centre for
Molecular Medicine, Berlin; Professor Riitta Lahesmaa, University of Turku; Professor Albert Heck, The Netherlands Proteomics Centre, Utrecht; Dr. Joe Lewis, Chemical Biology Unit, EMBL; Group leader Klaus Okkenhaug, Babraham Institute, Cambridge, UK; Dr.
Guillaume Pidoux, Université Paris Süd; Professor Bodo Grimbacher, Freiburg University; Dr. Julio Saez- Rodrigues, EMBL-EBI, Hinxton / Univ of Aachen, UK;
Professor Mikael Elofsson, MIMS, Umeå, Sweden, Dr.
Krister Wennerberg, FIMM, Helsinki, Finland, Professor Tobias Bopp, University of Mainz and others.
National collaborations
The group collaborates with Group Leaders Judith Staerk, J. Preben, Morth and Camila Esguerra
Biotechnology Centre / NCMM and Professors Heidi Kiil Blomhoff, Philippe Collas, Jo Klaveness, Arnoldo Frigessi, Bernd Thiede, University of Oslo; Professors Dag Kvale and Anne Ma Dyrhol-Riise, Dept. of Infectious Diseases, Senior Consultants Bjørn Atle Bjørnbeth and Sheraz Yaqub, Gastrosurgical Dept., Professor Ivar Sjaastad, Institute of Experimental Medical Research, Professor Guttorm Haraldsen, Dept. of Pathology, Professor Ludvig Munthe, Institute of Immunology, Professor Geir E. Tjønnfjord, Senior Consultants Ingunn Dybedahl and Fredrik Schjesvold, Dept. of Haematology, Professor Pål Aukrust Dr. Arne Yndestad, Professor Bente Halvorsen and Professor Tom Hemming Karlsen; Inst. of Internal Medicine Research, Professors Johanna Olweus and Kalle Malmberg, Dept of Immunology, Inst. for Cancer Res., Senior Consultant Jon Amund Kyte, Dept. of Oncology, and Professor Annetine Staff, Dept Ob-Gyn, Sen. Consultants Are Holm and Karl Otto Larsen, Dept of Lung Diseases, Oslo University Hospital; Professor James B. Lorens, University of Bergen, Professor Bjørn Tore Gjertsen, Senior Consultant Line Bjørge, Haukeland University Hospital, Bergen; Professor Anders Sundan, NTNU, Senior Researcher Geir Klinkenberg, SINTEF, Rafi Ahmad, Hedemark Univ. College and others.
cancer therapy, particularly looking at haematological malignancies. Furthermore, systems biology analyses are applied on the phospho-flow data from single cell signalling as well as from mixed cell populations with Treg immunosuppression.
The improved understanding of signalling networks can be applied to many disease states, including immune-de- ficiencies, inflammatory disorders and cancers and may promote the development of highly specific pharmaceu- ticals that maximise their therapeutic value, while mini- mising unwanted side-effects.
ACHIEVEMENTS IN 2016
• Professor Kjetil Taskén awarded the King Olav V’s Prize for Cancer Research 2016, for his work with immunotherapy.
• Paper in Journal of Clinical Oncology by Simer Bains et al attracted significant media attention, with over 100 press items generated.
Key Publications from the Taskén Group:
20+ papers were published in 2016/Q1 2017, including co-authored papers in Cell Reports and Leukaemia, both with an impact factor of around 10. Other highlights include the Group’s first paper on the CLL / cancer drug sensitivity screening (Parente-Ribes, Skånland et al) and a paper in the Journal of Leukocyte Biology (Chelappa et al) where the journal wrote an Editorial on our paper:
Parente-Ribes, A.*, Skånland, S.S.*, Bürgler, S.*, Os, A, Wang, D., Bogen, B., Tjønnfjord, G.E., Taskén, K.$,#, Munthe, L.A. $,# (2016)
Spleen tyrosine kinase inhibitors block CD40L induced proliferation of chronic lymphocytic leukaemia cells.
Haematologica, 101:e59-62.
Chelappa, S., Lieske, N.V., Hagness, M., Line, P.D., Taskén, K.,#Aandahl, E.M.# (2016)
Human regulatory T cells control TCR signalling and sus- ceptibility to suppression in CD4+ T cells.
J. Leukocyte Biol., 100:5-16. (#corresponding authors) - In section “Spotlight on Leading Edge Research”, Editorial: Jeschke & Williams. Treg potency and the importance of being fit. Ibid, 1-3.
Professor Kjetil Taskén was senior author on a report examining digital technology and its potential for facilitating faster research and development, and gen- erating value within Norway’s biology economy. The report, Digital Biology in Norway – Opportunities for Creating Value, Skills Needs, and Challenges in Economic Development, was published by Centre Digital Life Norway in March 2017.
Summary of grants awarded 2016/Q1 2017:
• Awarded a Cancer Society programme grant for 2017-2020 for the Taskén Group (6m NOK)
• Won a Helse Sør-Øst (Regional Health Authority for South-Eastern Norway) programme grant for 2017-2019 (4.5m NOK)
• Co-PI on a Cancer Society programme grant to fund our clinical trial on ASA intervention in colorectal can- cer (6m NOK) 2017-2020
• Co-PI on a KLINBEFORSK (Department of Health and Social Services) grant to fund Group’s clinical trial on ASA intervention in colorectal cancer (19m NOK) 2017-2021
• Awarded UiO Innovation grant for 2017-2018 (800k NOK)
PhD defences from the Taskén Group in 2016:
• Simer J. Bains
• Stalin Chelappa
• Nora V. Lieske
• Alexandra Dukic
Some 20+ talks were held nationally and internationally including:
• Research Council of Norway, Industry Day, April 19, 2016 in Det Norske Teatret. Speaker: Gene technology moves boundaries in medicine.
• 43rd Scandinavian Society for Immunology meeting, Turku, Finland, 2016
• 19th Annual Broegelmann Lecture, University of Bergen, 2016
• Int. Congress of Immunology, Melbourne, Australia, 2016
• Fifth International Meeting on Anchored cAMP-signal- ling pathways, Zermatt, Switzerland, 2016
• Norwegian Society for Oncology Annual Meeting, Trondheim, 2016
• Oslo Life Science Conference 2017, February 6, speaker.
• Kobe University Symposium, Kobe Japan, March 14, 2017. Invited Speaker. (This was tri-university collab- oration meeting – We have signed a MOU with Kobe and U Washington in Seattle).
FUNDING
In addition to support from NCMM and the Biotechnology Centre of Oslo, the Taskén Group has, in 2016, received support from:
• University of Oslo – Digital Life funding
• The Research Council of Norway
– including Biotek2021, NOR-OPENSCREEN
• The Norwegian Cancer Society
• Helse Sør-Øst
• Norwegian Department of Health and Social Services
• European Commission
– including EATRIS, EU-Openscreen
• Novo Nordisk Foundation
• Jebsen Centre for Cancer Immunotherapy
• Jebsen Inflammation Research Centre
Prostate cancer is a high-incidence cancer in men with progression to metastatic disease occurring in around 20-30% of detected cases. Major translational challenges include the development of biomarkers able to pre- dict progression at the time of diagnosis and treatment response/failure as well the need to develop more effec- tive treatment strategies. Our strategy for addressing this has been to explore how transcription factors and chromatin change in transformed cells and how the gene networks that they regulate map back to clinical expres- sion profi les. From the resultant gene networks and path- way enrichments we have identifi ed biological processes that we believe are important to regulate progression and treatment response and have gone on to study these functionally and, with clinical collaborators, to evaluate candidate biomarkers. From this work the main biolog- ical focus of the group is on stress response signalling, sub-divided broadly into glycosylation and the unfolded protein response/autophagy. In particular, we are focus- sing on how genes that function in these processes confer resistance to therapeutic and oncogenic stress and how they can be targeted therapeutically.
DESCRIPTION OF THE GROUP’S RESEARCH
Chromatin biology and transcriptional regulation:Predominantly we employ high-throughput sequencing and transcript profi ling to map genome-wide changes in transcription factor recruitment and chromatin com- paction in cell-lines and clinical samples. By using these approaches we have found that chromatin opening is a hallmark of lethal castrate-resistant disease and that the activity of a key transcription factor in prostate cancer, the androgen receptor (AR), is modifi ed by the expres- sion of other oncogenic transcription factors with a focus here principally on c-Myc. Additionally, we have found
that regions of open chromatin are hotspots for prostate cancer risk loci.
Autophagy:
Autophagy (‘self-eating’) is a key stress response that can have pro-survival or pro-apoptotic properties in cancer cells depending on the context and trigger. Whilst this has been recognised by groups worldwide, the desire to achieve clinical translational endpoints through the study of autophagy has led to the over-interpretation of assays and autophagic markers. A key contribution that we are making in this area is to carefully dissect whether auto- phagic markers are also necessary to drive the functional biology of the autophagic process. We are addressing this by developing and qualifying autophagic assays and then testing the impact of genetic targeting of autophagic factors. With that knowledge in place the programme will then move on to explore how these factors affect response to treatments such as anti-androgens.
Glycosylation:
Glycosylation is a bridge between metabolic changes, pro- tein folding capacity and in turn the stability and activity of oncogenes. We realised the potential importance of glycosylation early in the development of our research program based on clinical profi ling and mapping of tar- get genes for the androgen receptor and other transcrip- tion factors. In particular, we have been exploring how a pathway called the hexosamine biosynthesis pathway affects the stability of c-Myc and other oncogenes and the response to activators of the unfolded protein response.
This pathway is fuelled by metabolites drawn from all of the core metabolic processes in the cell to form a single amino-sugar-nucleotide conjugate – UDP-GlcNAc. Whilst heightened activity of this pathway is required to sustain protein folding in untransformed secretory cells, the same pathway can also confer resistance to environmen-
Ian G. Mills
Prostate Cancer
Research Group
RESEARCH GROUPS: IAN G. MILLS RESEARCH GROUPS: IAN G. MILLS
tal stress and consequently the expression and activity of enzymes in the pathway and fuelled by the pathway are retained and amplified in cancer cells.
Biomarkers:
Since prostate cancer progresses in a subset of diagnosed cases to a lethal metastatic disease and the current bio- marker, prostate specific-antigen (PSA), is relatively ubiq- uitous, there is a significant need for biomarkers that flag heightened risk of disease progression. We are evaluating transcripts and proteins as candidate biomarkers, focus- sing predominantly on ‘liquid biopsy’ (urine, blood and circulating tumour cells). Amongst these sample types we have so far made most progress in evaluating mark- ers in blood samples. Since it typically takes 5-10 years from diagnosis to disease progression, blood samples represent a sample type that currently has the longest follow-up time having been biobanked. By contrast, urine sample collections are still relatively recent and there remains controversy over the best detection platform for circulating tumour cells. The biomarkers that we have been testing have arisen from three sources. Transcript biomarkers have either been derived from our pre-clin- ical studies or through collaboration with international research consortia. Protein biomarkers have arisen from proteomic profiling of Janus Serum Bank samples and downstream validation in samples obtained from other Nordic and UK sample collections through collaboration.
ACHIEVEMENTS IN 2016/Q1 2017
• Professor Per Seglen (Guest Researcher)
– will be awarded the King Olav V’s Prize for Cancer Research 2017 in June, in recognition of his seminal 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.
FUNDING
In addition to support from NCMM, the Mills Group has, in 2016, received additional support from:
• The Research Council of Norway – Young Talent Award to Nikolai Engedal, and FIRMEDBIO
• Helse Sør-Øst – three-year postdoc position for Dr.
Alfonso Urbanucci
• Movember/Cancer Society Team Science Award
• The Norwegian Cancer Society – Funding for three years, for two postdocs
GROUP MEMBERS
Head EngineersIngrid Jenny Guldvik (until June 2016) Frank Sætre (until July 2016)
Senior Researcher Nikolai H. Engedal Guest Researcher Per O. Seglen
Postdoctoral Fellows Harri Itkonen
Alfonso Urbanucci PhD Fellows
Lisa Gerner (until February 2017) Morten Luhr
Bertrand Simon – Joint PhD student at EMBL Hamburg (until March 2017)
Paula Szalai
COLLABORATIONS
Thorsten Schlomm, Eppendorff Hospital, Hamburg, Germany (Biomarkers)
Henrik Gronberg/Fredrik Wiklund, Karolinska Institute, Sweden (Biomarkers)
David Neal, Cambridge University, UK (Biomarkers) Kristin A. Taskén, OUS/UiO (Biomarkers)
Ole Andreassen, OUS/UiO (Genetic risk)
Fahri Saatcioglu, OUS/UiO (Stress response signalling) Preben Morth, NCMM
(Calcium/calmodulin-dependent kinases in cancer) Judith Staerk, NCMM
(Epigenetics in haematological malignancies) Toni Hurtado, NCMM (Transcriptional regulation in hormone-dependent cancers)
Ole Petter Rekvig, University of Tromsø, Norway (Lupus markers and biology in cancer)
Wolfgang Lilleby, OUS (Biomarkers)
Suzanne Walker, Harvard University, Massachusetts, USA (OGlcNAc Transferase)
Angelo DeMarzo, John Hopkins University, Maryland, USA (c-Myc)
Paul Rennie/Ladan Fazli,
Prostate Cancer Centre, Vancouver, Canada (Signalling and biomarkers in prostate cancer) Matthias Wilmanns, EMBL Hamburg, Germany (Calcium/calmodulin-dependent kinases in cancer) Tapio Visakorpi, University of Tampere, Finland (Chromatin biology and androgen receptor signalling in prostate cancer/biomarkers)
Andrei Chabes, MiMS/University of Umeå, Sweden (Nucleotide biosynthesis)
Yvonne Ceder, Lund University, Sweden (Non-coding RNA in prostate cancer) Anne Simonsen, UiO (Autophagy)
Maria Theresa Landi, National Cancer Institute, Maryland, USA (Genetic risk – lung cancer)
Olli Kallioniemi/Paivi Ostling, SciLife Lab/Karolinska Institute, Sweden (Screening to identify sensitisers to anti-androgens)
Poul Nissen, DANDRITE/Aarhus University, Denmark (SERCA inhibition and autophagy)
Lorena Arranz, University of Tromsø, Norway (Transcriptional regulation in haematological malignancies)
The Morth group employs a structural systems biology approach to investigate the proteins involved in acid- base homeostasis and metal ion transport across the cellular membrane. A variety of techniques are used in order to identify and characterise both soluble and membrane bound proteins involved in pH regulation.
A bioinformatics approach is used to target new pro- teins and interaction partners of interest. Furthermore, X-ray crystallography and several biophysical methods to obtain structural information as well as biochemical techniques are also used, including activity assays and fluorescence spectroscopic measurements.
DESCRIPTION OF THE GROUP’S RESEARCH
To study the 3D atomic structure of membrane proteins, the group is currently developing purification and lipid vesicle reconstitution protocols. The aim is to purify and characterise these membrane proteins.
The bicarbonate transporters
Acid-base homeostasis is fundamental to our under- standing of human physiology and is essential to cel- lular function. The main buffering system found in the human body is based on bicarbonate. The SLC4 proteins are the main facilitators of bicarbonate transport across the plasma membrane, however, not much is known about the structural basis of function and regulation of these. The N-terminal cytoplasmic domain (NTD) of the sodium-coupled chloride bicarbonate exchanger (NCBE), found predominantly in the choroid plexus of the brain, has been cloned, expressed and purified. The core domain found centrally in the NTD has been crys- tallized and the structure determined at 4.0 Å resolution.
The NTD of NCBE is found to contain regions of intrinsic protein disorder and these disordered regions are con- served among all bicarbonate transporters of the SLC4 family. The disordered regions coincide with regions of sequence variation, indicating that although sequence is not conserved, the disorder is.
P-type ATPases in infectious diseases
The system is strongly dependent on the ion gradients maintained by the P-type ATPases. The group therefore aims to develop a complete structural model for anion transport and recognition. Structural analysis of P-type ATPases will continue with focus on the prokaryotic Ca2+ ATPases and Mg2+ ATPases. In particular, we are focusing on their function as participants in viru- lence systems. The systems in question originate from Listeria monocytogenes and Salmonella typhimurium, and our work on translation in infectious diseases like 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 allow direct inclusion into the exciting drug screening platforms in Europe. Furthermore, these projects can benefit the broad scientific community located in Oslo, focusing on infectious diseases.
Characterisation of supramolecular Tankyrase complexes implicated in colorectal cancer, using an intrinsically disordered protein as bait.
A translational project focusing on identification of large supramolecular complexes implicated in the Wnt pathway was initiated by the Morth group. We are performing structural studies of a human ADP- ribosyltransferase tankyrase (TNKS), trying to identify novel direct interaction partners by using a proteomics approach in collaboration with Bernd Thiede (UiO).
Tankyrases belong to the poly (ADP-ribose) polymerase (PARP) superfamily and are involved in various cellular functions such as telomere maintenance, centrosome maturation, Wnt signalling, embryonic development and the pathogenesis of Cherubism. We are currently aiming to isolate and characterise proteins that bind to the full length tankyrase enzyme, a protein of more than 1200 residues and with several potential and ver- ified interaction partners. We are therefore combining our structural and biochemical studies with cellular assays, using the strong imaging platforms built up by Oddmund Bakke (UiO).
Membrane
Transport Group
J. Preben Morth
RESEARCH GROUPS: J. PREBEN MORTH
ACHIEVEMENTS IN 2016
Publications from the group:Bauer J, Bakke O, Morth JP. Overview of the mem- brane-associated RING-CH (MARCH) E3 ligase family.
N Biotechnol. 2016 Dec 14. pii: S1871-6784(16)32629-2.
doi: 10.1016/j.nbt.2016.12.002. [Epub ahead of print]
PubMed PMID: 27988304.
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- tion of human recombinant CaMKK2 in complex with calmodulin in Escherichia coli. Data Brief. 2016 Jun 29;
8:733-40. doi:10.1016/j.dib.2016.06.033. eCollection 2016 Sep. PubMed PMID: 27508226; PubMed Central PMCID:
PMC4950174.
Bjerregaard-Andersen K, Østensen E, Scott JD, Taskén K, Morth JP. Malonate in the nucleotide-binding site traps human AKAP18γ/γ in a novel conformational state.
Acta Crystallogr F Struct Biol Commun. 2016 Aug; 72(Pt 8):591-7. doi:10.1107/S2053230X16010189. Epub 2016 Jul 13. PubMed PMID: 27487922; PubMed Central PMCID:
PMC4973299.
Leo JC, Oberhettinger P, Yoshimoto S, Udatha DB, Morth JP, Schütz M, Hori K, Linke D. Secretion of the Intimin Passenger Domain Is Driven by Protein Folding.
J Biol Chem. 2016 Sep 16; 291(38):20096-112. doi: 10.1074/
jbc.M116.731497. Epub 2016 Jul 27. PubMed PMID:
27466361; PubMed Central PMCID: PMC5025694.
Hong Z, De Meulemeester L, Jacobi A, Pedersen JS, Morth JP, Andreasen PA, Jensen JK.
Crystal Structure of a Two-domain Fragment of Hepatocyte Growth Factor Activator Inhibitor-1:
FUNCTIONAL INTERACTIONS BETWEEN THE KUNITZ- TYPE INHIBITOR DOMAIN-1 AND THE NEIGHBORING POLYCYSTIC KIDNEY DISEASE-LIKE DOMAIN.
J Biol Chem. 2016 Jul 1; 291(27):14340-55. doi: 10.1074/
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 recombi- nant 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 cardi- olipin 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.
FUNDING
In addition to support from NCMM, Morth Group has, in 2016, received additional support from:
• The Norwegian Cancer Society
• The Research Council of Norway
• Marie Curie
• NordForsk
GROUP MEMBERS
Principal Engineer Bojana SredicPostdoctoral Fellows Johannes Bauer
Harmonie Perdreau-Dahl Saranya Subramani PhD Fellow
Julia Weikum (from April 2017) Students
Annika Kratzel, Erasmus Student (April - July 2017) Maria Wahle (May - September 2017)
COLLABORATIONS
Oddmund Bakke, Department of Biosciences, UiO Sandip Kanse, Institute of Basic Medical Sciences, UiO Maria Eugenia Chollet Dugarte, Oslo University Hospital Grethe Skretting, Oslo University Hospital
Maria Skepo, Lund University, Sweden Lise Arleth, Copenhagen University, Denmark Michael Palmgren, Copenhagen University, Denmark Kresten Lindorff-Larsen, Copenhagen University, Denmark
Michele Cascella, Department of Chemistry, UiO William Louch, Oslo University Hospital (Ullevål)
The main interest of the group is to understand the mechanism of hormone resistance in breast cancer.
Moreover, we are interested in determining how the estrogen antagonist Tamoxifen contributes to the inhibi- tion of breast cancer progression. Therefore, the focus of my future research is summarised in two main projects:
(1) Elucidating the role of cell-signalling pathways con- trolling FOXA1 functions in Breast Cancer (2) Searching for novel mechanisms of action for the anti-ER drug Tamoxifen.
DESCRIPTION OF THE GROUP’S RESEARCH
Elucidating the role of cell-signalling pathways controlling FOXA1 functions in Breast CancerResistance to endocrine therapy is complex, heterogene- ous and may differ from patient to patient. The majority of clinical trials thus far have focused on combining or alternating endocrine therapy agents, or intercalating targeted therapies against kinase inhibitors such as CDK, PI3KAKT-mTOR, EGFR or HER2. However, cancer cells can eventually find other means to proliferate, and therefore escape the arrest imposed by these treatments.
For instance, treatment with AKT inhibitors has been shown to induce activation of SGK1, which continues to support cell proliferation (Castel, Cancer Cell 2016).
Having seen that FOXA1 was an important mediator of HER2/HER3 signalling (Gilfillan, Nat Communication in resubmission), we decided to study how other pathways with implications in cell proliferation could regulate its function. Our final goal is to better understand the mech- anisms that lead to resistance to current treatments and that are mediated by FOXA1. To test whether other kinases impact FOXA1 function, we have carried out a drug screening using a selected subset of kinases and phosphatases with known implications in breast cancer,
and analysing their effect on FOXA1 activity.
Subsequently, we performed the chemical screening in hormone-sensitive and hormone-resistant cell lines, which were positive for the expression of FOXA1. We identified 23 potential kinases targeting FOXA1. Next, we repeated the drug screening with 45 inhibitors targeting these kinases. As a proof of principle, with this system we could confirm our previous results regarding the reg- ulation of FOXA1 by the HER2 pathway. Taken together, 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- nals of these kinases in the control of proliferation for hormone-resistant patients.
Searching for novel mechanisms of action for the anti- ER drug Tamoxifen
To date, the precise mechanism of action of Tamoxifen is not completely understood, mainly due to the fact that the current studies on the molecular characterisation of tamoxifen action are based on the idea that those compounds target exclusively ER (Shang, Cell 2000).
However, the more we understand about the molecular mechanisms of other drugs targeting other proteins, the more we realize that they are generally promiscuous with regard to their biological targets and effects. Hitting multiple targets can enable a drug to be applied thera- peutically in several potentially unrelated diseases; or, if more than one of the drug’s targets is involved in path- ways relevant to a particular disease, the drug may have increased efficacy for this therapeutic application. For instance, the anti-ER drugs Tamoxifen and Fulvestrant increase Bcl-2 levels and inhibit growth of breast car- cinoma cells by modulating PI3K/AKT, ERK and IGF-1R pathways independently of ER (Long, JBC 2006).
Antoni Hurtado
Breast Cancer
Group
RESEARCH GROUPS: ANTONI HURTADO
In this study, we aimed to identify targets relevant for Tamoxifen repressive action. We used a chemical pro- teomics approach, which allows the identifi cation of drug targets. Next, we performed proteomics to identify novel Tamoxifen-interacting proteins and compared to protein targets of ER-tamoxifen. Importantly, this targeted pro- teomics approach revealed that 50% of the Tamoxifen- biotin pulled down proteins were also identifi ed within the ER-Tamoxifen pull down, which confi rmed the suit- ability of this method to identify Tamoxifen-interacting proteins.
In addition, we have also identifi ed other proteins not pres- ent within the list of ER-interacting proteins. Tamoxifen- associated proteins identifi ed at least in two replicates and excluded from the negative control (biotin beads) were considered as positive hits. Among these Tamoxifen ER-independent targets we have identifi ed the protein SKIP, which is an important modulator of TGF-beta/Smad signalling. Previously, it has been reported that ER and TGFbeta signalling have opposite roles in proliferation and apoptosis. Whereas ER induces a transcriptional pro- gram that triggers proliferation and inhibits apoptosis, TGF-beta induces cell growth arrest and promotes apop- tosis (Band, Mammary Gland Biology Neoplasia 2011).
Moreover, their regulatory pathways intersect, and ER blocks TGF-beta pathway by multiple means, including direct interactions of its signalling components Smads (Band, Mammary Gland Biology Neoplasia 2011).
Considering the intricate roles of these major signalling pathways in mammary epithelial cells biology and tum- origenesis, and their extensive interactions, we are cur- rently investigating how Tamoxifen regulates the cross- talk between these pathways.
ACHIEVEMENTS IN 2016
• Paper published in Nucleic Acids Research (NAR) by Elisa Fiorito (PMID: 27638884); Hurtado lead author
• The manuscript ‘Breast tumours escape endocrine therapy by ER-independent mechanisms triggered by the coordinated activities of HER2/3 and deacetyl- ated FOXA1’ by Gilfi llan et al is re-submitted to Nat Communications
• The manuscript ‘DNA methylation at enhancers distin- guishes distinct breast cancer lineages’ by Fleischer et 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.
FUNDING
In addition to support from NCMM, the Hurtado Group has, in 2016, received additional support from:
• The Norwegian Cancer Society
• EU FP7-PEOPLE-2013 COFUND - Sciencia Fellow programme
• Research Council of Norway - Frimedbio Young Talent programme
• Helse Sør-Øst (HSØ) - Open Project
GROUP MEMBERS
Head Engineer Siv Gilfi llanPostdoctoral Fellows Anne Marthe Fosdahl
Sachin Kumar Singh (from September 2016) Venkata Sateesh Somistetty (until January 2017) PhD Fellow
Shixiong Wang MSc Student Neus Daviu
(Erasmus student, September 2016-April 2017)
COLLABORATIONS
Dr. Therese Sørlie, Oslo University Hospital Prof. Camilla Krakstad, University of Bergen
and Haukeland University Hospital, Bergen, Norway Prof. Vessela Kristensen,
Oslo University Hospital Dr. Preben Morth, NCMM Dr. Minna U. Kaikkonen, University of Eastern Finland Dr. Meritxell Bellet,
Vall-Hebron Research Institute, Barcelona, Spain Dr. Jason Carroll, CRI-CRUK, Cambridge, UK Dr. Maurizio Scaltriti,
Memorial Sloan Kettering Cancer Center, NY, USA
The Staerk Group focuses on deciphering molecular pro- cesses that govern hematopoietic specification, hemato- poietic stem cell (HSC) renewal and differentiation as well as formation of mature blood cells. Understanding the mechanisms governing blood development is needed to decipher the underlying molecular events that drive lifelong formation of blood cells, and to identify path- ways that are dysregulated in blood disorders.
The overall goals of the group’s research are to: i) func- tionally characterise epigenetic and genetic factors and signalling pathways during hematopoietic development, ii) decipher the mechanism by which the nuclear lamina modulates hematopoietic development, and iii) identify underlying molecular causes of myeloid blood disorders triggered by defects in lineage differentiation that the group studies in the physiologic setting. To achieve these goals, the group is using human pluripotent stem cells, in vitro differentiation assays, as well as animal models along with primary patient samples. The group combines these assays with genetic and genomic approaches.
DESCRIPTION OF THE GROUP’S RESEARCH
Epigenetic dynamics during blood cell differentiation One focus of the group is to understand how epige- netic signatures influence cell fate determination dur- ing mesoderm and hematopoietic cell specification.DNA methylation is an epigenetic modification, which is key to numerous processes, including regulation of gene expression and maintaining genomic integrity.
Additional complexity to the overall gene regula- tion has been added by the discovery of Ten-Eleven- Translocation (TET) enzymes, which are dioxygenases that catalyse the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). The group char- acterised 5hmC distribution in CD34+ cells, and mature blood lineage cells. Our results showed that in CD34+
cells, 5hmC primes expression of genes regulating mye- loid and lymphoid lineage commitment. Moreover, in CD34+ cells, 5hmC at enhancers was associated with increased binding of RUNX1 and FLI1 that are TFs cru- cial for haematopoiesis. To further investigate the role of 5hmC during human blood cell differentiation, the group established oxBS-seq and deleted endogenous TET2 and/or TET3 in hESC lines that encode reporter genes to monitor blood cell differentiation.
Projects with translational impact
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterised by impaired haematopoiesis and a predisposition to devel- oping acute myeloid leukaemia (AML). The underlying cause for MDS is incompletely understood. The group is using primary patient samples as well as patient-de- rived induced pluripotent stem cells to analyse the potential of these iPSC to differentiate into hematopoi- etic progenitors, and to screen transcription factor and miRNA libraries to identify candidate genes to reverse the potential block in in vitro blood cell differentiation.
Chronic lymphocytic leukemia (CLL) is a common hema- tological cancer in adults and is characterised by clonal B cell expansion. In the past year, the group assessed cell cycle defects in CLL, and found that a significant num- ber of CD19+ B cells isolated from peripheral blood CLL samples are arrested in cytokinesis. The group linked the observed cytokinesis arrest to reduced NuMA and p53 protein levels, and showed that proteins known to be crucial for cell division, checkpoint and centromere function were dysregulated.
Lamin proteins and haematopoiesis
More recently, the Staerk group has developed an inter- est in the nuclear lamina (NL)/lamin proteins. Lamins are divided into A-type lamins that are expressed in most somatic cell types, but are not expressed in stem cells,
Stem Cell Group
Judith Staerk
RESEARCH GROUPS: JUDITH STAERK
while B-type lamins (LMNB1 and LMNB2) are highly expressed in both, stem cells and differentiated cell types. Apart from the well-established role in forming a scaffold underneath the inner nuclear membrane, the NL has been implicated in nuclear positioning of chro- matin and transcriptional regulation, which is thought to be critical for cell fate decisions. Moreover, recent studies show that a mutation in lamin A/C (LMNA) leads to altered distribution of histone H3 lysine 27 trimethyla- tion (H3K27me3) in fi broblasts, implicating the interplay between the NL, the epigenetic landscape and probably also direct interaction with epigenetic enzymes. When the process of characterising changes of NL components more closely was started, the group was surprised to fi nd very few studies addressing lamin protein function 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 proteins affect human blood development.
ACHIEVEMENTS IN 2016
PublicationsTekpli X, Urbanucci A, Hashim A, Vågbø CB, Lyle R, Kringen MK, Staff AC, Dybedal I, Mills IG, Klungland A, 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
GROUP MEMBERS
Principal Engineer Kirsti E. Præsteng Postdoctoral Fellows Theresa Ahrens Safak Caglayan Artur Cieslar-Pobuda Adnan Hashim Marie Rogne PhD FellowsJulia Madsen-Østerbye Oksana Svärd
COLLABORATIONS
Stefan N Constantinescu, Ludwig Institute for Cancer Research, Brussels, Belgium
Petr Bartunek, Institute of Molecular Genetics, Prague, Czech Republic
Karl-Johan Malmberg, OUS/UiO Geir Tjønnford, OUS
Ingunn Dybedal, OUS
PHOTO: JO MICHAEL
The Mathelier Group develops and assesses computa- tional methods to analyse genomic sequences (DNA).
The goal of the group is to create the next generation of cutting-edge algorithms and open computational biology software, with immediate application to real-life biologi- cal problems.
DESCRIPTION OF THE GROUP’S RESEARCH
The group’s computational biology research program aims at furthering the understanding of gene expression regulation (when and where genes are expressed), and the mechanisms by which it can be disrupted in human diseases such as 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
mutations within TF binding sites can alter gene expres- sion, triggering human diseases such as cancer.
As successful computational biology research relies on high quality data for which the group has a strong under- standing, work is currently focused on combining large amounts of experimental data with in house computa- tional models to identify the binding sites of TFs. This work will provide the group with a critical map of where TFs bind in the human genome for further studies.
The group next plans to combine whole genome sequenc- ing and gene expression data from cancer patient sam- ples with its high-quality regulatory map. This will provide new insights into the predictions of the impact of the mutations dysregulating gene expression and con- tributing to cancer.
Computational Biology and Gene Regulation
Anthony Mathelier
RESEARCH GROUPS RESEARCH GROUPS: ANTHONY MATHELIER
ACHIEVEMENTS IN 2016
Lab started in May 2016; early hires include a PhD stu- dent and a Postdoctoral Fellow.
Publications
• A. Khan and A. Mathelier.
Intervene: a tool for intersection and visualization of multiple gene or genomic region sets.
bioRxiv, 2017. https://doi.org/10.1101/109728
• C.-H. Lecellier, W.W. Wasserman, R. Rohs, and A.
Mathelier. Human enhancers associated with immune response harbour specific sequence composition, activity, and genome organization. bioRxiv, 2016.
https://doi.org/10.1101/078477
• 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, J.A. Ramilowski, O. Rackham, J. Gough, R. Andersson, A. Sandelin, H. Ienasescu, H. Ono, H. Bono, Y.
Hayashizaki, P. Carninci, A.R.R. Forrest, T. Kasukawa*
and H. Kawaji*. Update of the FANTOM web resource:
high resolution transcriptome of diverse cell types in mammals.
Nucleic Acids Research, 2016. doi: 10.1093/nar/gkw995
• A. Mathelier, B. Xin, T.-P. Chiu, L. Yang, R. Rohs, and W.W. Wasserman. DNA Shape Features Improve Transcription Factor Binding Site Predictions In Vivo.
Cell Systems, 2016. doi:10.1016/j.cels.2016.07.001
• D.J. Arenillas, A. Forrest, H. Kawaji, T. Lassman, the FANTOM consortium, W.W. Wasserman+, and A.
Mathelier+. CAGEd-oPOSSUM: motif enrichment anal- 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.
FUNDING
Support received from NCMM
GROUP MEMBERS
Postdoctoral Fellow Aziz KhanPhD Student Marius Gheorghe Master Student
Eleftherios Pavlos (Erasmus student, Oct. 2016-Mar. 2017)
COLLABORATIONS
Vessela Kristensen, Oslo University Hospital Hege Russness, Oslo University Hospital
Benoît Ballester, French Institute of Health and Medical Research, Paris, France
Charles-Henri Lecellier, Institute of Molecular Genetics of Montpellier, France
FANTOM consortium (JASPAR project) Groups of:
Wyeth Wasserman, University of British Columbia, Vancouver, Canada
Boris Lenhard, Imperial College London, UK Albin Sandelin, Copenhagen University, Denmark
The Group’s main research interest is the study of cell cycle regulation, in particular transitions into and out of mitosis. Classically, the focus of attention in the field has been on understanding the processes regulated by protein kinases (especially Cyclin-Dependent Kinases or CDKs) and on how their activity is temporally and spa- tially regulated for an ordered cell cycle progression.
In our laboratory, however, we are interested in the role of the CDK opposing activity, that is, protein phos- phatases. We focus our efforts in studying the processes regulated by protein phosphatases that are relevant to cell cycle progression, and that could have a repercus- sion on our understanding of the cell cycle.
DESCRIPTION OF THE GROUP’S RESEARCH
Cell cycle control is very intricate; it is modulated by external and internal stimuli, and transitions between the different phases are prompted by the engagement of feedback loops. Although phosphatase activity has been assumed to participate in this control, its role has been commonly regarded as non-regulated. This per- ception is, however, changing, and new data is accu- mulating in favour of a controlled phosphatase activity timing the events of the cell cycle.
Nevertheless, protein phosphatases are still difficult to study due to their pleiotropic effects in the cell and, in this regard, the use of more simple organisms is key to understand their basic functions. With this idea in mind, we have developed our research using a yeast model, Schizosaccharomyces pombe, and looking at individual phosphatase complexes during specific phases of the cell cycle or cellular responses. In trying to simplify the picture that we are studying, we can achieve a clearer view of the essential functions of these phosphatases and ultimately extrapolate them to more complex scenarios.
More specifically, we are interested in understanding:
Regulation of mitotic progression by protein phosphatases, particularly type-2A phosphatases We examine the role of phosphatase activity in the ordering of Cdk-substrates dephosphorylation, as well as in the engagement of feedback loops that lead to the irreversible inactivation of Cdk complexes during mitotic exit. We also investigate how phosphatase activity influ- ences the behaviour of cells during a sustained mitotic arrest. Since cells arrested in mitosis for long periods eventually undergo programmed cell death, understand- ing the mechanisms that can prolong this arrest will be instrumental in order to improve the efficacy of current cancer treatments.
Interplay between phosphatase activity and signalling pathways regulating cell growth and differentiation We have shown that the phosphatase PP2A-B55 plays an important role in connecting the activities of the two TOR complexes, TORC1 and TORC2. This becomes par- ticularly relevant during nutritional deprivation, a sig- nal that in yeast leads to cellular differentiation. Given this special relation between TOR signalling and PP2A, we are now studying the implication of PP2A activity in other processes regulated during nutritional stress by TOR signalling. In particular, we are addressing the involvement of PP2A in the regulation of protein transla- tion, as well as in the regulation of epigenetic marks and gene transcription.
Mechanisms controlling cell cycle arrest during cellular differentiation
In yeast as in mammals, cell differentiation can only occur if cells have previously stalled their progression through the cell cycle in G1 phase. Hence, differentiation signals control the activity of key proteins involved in cell division. We are trying to understand the mecha- nisms that lead to this control, specifically in the context 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.
