From disease mechanisms to clinical practice

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From disease mechanisms to clinical practice

10

_YEARS

NCMM

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NCMM-affiliated Publications and Press items

Personnel

60 68 42

Research Highlights

44

52 News and Events 2017

48 Scientific Advisory Board

56 NCMM Board

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Recent progress: A review of 2017 We started 2017 with the official completion of the merger between BiO (Bio- technology Centre of Oslo) and NCMM in January. This was a particular landmark for NCMM, and the decision has helped to create a more robust centre with a stronger technology base. It has also helped to rein- force our funding base and our standing as a national centre that conducts translational and molecular medicine research.

Another highlight for 2017 was the recruitment of our new Assistant Director, Hartmut Luecke, a leading structural biologist. Professor Luecke started at NCMM in November 2017 and is now in the process of establishing his group.

In terms of our scientific outputs, NCMM’s group leaders have reported some 60 scientific NCMM-qualified papers published in 2017 and 2018. This includes papers in jour- nals such as the Journal of Experimental Medicine, Nature Communications, Leuke- mia, Cell Metabolism, and many more.

NCMM also lists over 20 on-going observa- tional and interventional clinical studies in the areas of therapy and disease mechanisms, as well as in the areas of molecular markers, diagnostics and monitoring.

An increasingly collaborative research network

NCMM has been able to further expand its research network, thanks to the appointment of six new Associate and five new Young Associate Investigators in Novem- ber 2017. These appointments mean that we can continue to further strengthen our links to outstanding researchers across the whole of Norway, and to build on our knowledge base in molecular and translational research.

We were able to hear more about some of the current collaborative projects, made possible through seed-money funding from NCMM in 2017, between our Associate and Young Associate Investigators and NCMM group leaders at our annual NCMM network meeting in February 2018. You can read more about the network and resulting collaborative projects later in this report.

Outside of this network, on a European and international level, NCMM group leaders now report over 120 collaborations, of which over 50 are international.

Nordic EMBL Partnership for Molecular Medicine

Our interactions with the Nordic EMBL Partnership for Molecular Medicine also continue to grow. The Partnership met in September 2017 for a very enjoyable and productive annual meeting, hosted by FIMM (Institute for Molecular Medicine Finland) in Helsinki. It is always inspiring and en- couraging to see so many scientists and staff from all levels come together to engage with one another, and to form connections with their peers across the network.

NCMM will host the 2018 Partnership meeting on 11-14 September in Oslo; a meeting which I am sure will be another excellent opportunity for the Nordic EMBL network to come together for a great scientific and networking programme.

Looking to the future

With the recruitment of Hartmut Luecke, NCMM is now working to create a Struc- tural Biology Hub which, alongside the Luecke Group, will include one to two other groups at the centre. We want to stay at the forefront of developments in this field, both scientifically and with respect to financing and establishing new national

infrastructures, such as for cryo-EM. In addition, structural biology fits perfectly into NCMM’s precision medicine strategy by providing the framework with which to understand the functional consequences of disease-causing mutations in somatic cells.

We are also working to build up NCMM’s expertise in bioinformatics. Expanding on this, we are in the process of recruiting two new group leaders; one in Systems Medicine and another in Precision Medicine. These recruitments will help us to continue our strong line of research into disease mechanisms, whilst allowing us to continue to focus on translational research studies.

Finally, NCMM will undergo its second external evaluation, organised by the Re- search Council of Norway, in Spring 2018.

This evaluation will assess the scientific quality of our research, and also the strategic role we play as a national research centre. After the evaluation, we are aiming to fully secure our funding base for a new five-year period. We also hope to see the ownership of NCMM extend to include more of Norway’s regions.

March 2018

Professor Kjetil Taskén NCMM Director

"We started 2017 with the official completion of the merger between BiO (Biotechnology Centre of Oslo) and NCMM in January. This was

a particular landmark...the decision has helped to create a more robust centre with a stronger technology base"

Overview by the Director –

Dear friends, colleagues, and supporters of NCMM. I am proud to present the 2017 NCMM Annual Report. This report gives an overview of our activities from the past year, with some insight into the centre’s progress and achievements as we enter our 10th year of operations.

As many of you will know, I will step down from my role as Director at the end of June 2018. It has been a great pleasure, and a privilege, to have spent the last 15 years as Director, supporting the strategic efforts of the University of Oslo to build an international research centre that uti- lises the EMBL model for recruitment of young group leaders. Initially as Director

of the Biotechnology Centre of Oslo from 2003, and then as the founding Director of NCMM. It has also been great fun to run what I have called a ‘greenhouse’ for young scientists, and to follow many young group leaders on their journey from recruitment to NCMM, up until their rotation out to faculty positions.

I therefore want to take this opportunity to thank you all for your support and contributions to the centre over the past decade. I really look forward to seeing how NCMM will further develop and grow in the coming years.

Photo: Trond Isaksen

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Greetings from the Faculty of Medicine

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The Faculty of Medicine is extremely proud to have hosted NCMM since April 2015. The strong scientific foundations that NCMM established with its launch in 2008 have now grown into a successful national research Centre, which is home to a number of excellent group leaders.

NCMM’s ability to recruit these outstanding international group leaders means that, once the group leaders have successfully completed their posts at the Centre, both Faculty departments and hospital departments benefit from access to a wider and more diverse talent pool from which to recruit from.

As recommended by the report from the Husebekk Commission in 2016, the need for Norway’s universities and regional health authorities to strengthen their coordi nation is increasing. I feel that NCMM, being hosted by UiO and co-funded by South-Eastern Norway Regional Health Authority (HSØ), is a model example of how these regional health authorities and universities can work together.

The extensive network offered by NCMM’s Associate and Young Associate Investigator programme means that the Faculty is better connected than ever to Norway’s other universities, hospitals, and regional health authorities. I had the pleasure of hearing some of the most recently appointed Associ- ate and Young Associate Investigators speak at the NCMM Network Meeting 2018 and was impressed by the breadth and quality

of research taking place within this grow- ing network. We also very much value the links that NCMM gives us to the European Molecular Biology Laboratory (EMBL), and to the three other Nordic EMBL partners.

Looking to the future, we hope to see the ownership of the Centre expand into more of Norway’s regional health authorities. An expanded ownership would mean that more regions are able to join in with, and benefit from, NCMM’s successes in molecular and translational medicine.

The Centre has also proven to be successful at attracting external funding, and more shared ownership would mean even greater successes and opportunities for funding;

something that I see as extremely important in light of the Faculty’s focus in this area.

NCMM’s first external evaluation in 2013 declared the Centre to be a huge success, and we expect the second evaluation, due in mid-2018, to echo these findings.

On behalf of the Faculty of Medicine, Frode Vartdal, Dean

"I feel that NCMM, being hosted by UiO and co-funded by South-Eastern Norway Regional Health Authority (HSØ), is a model example of how these regional health authorities and universities can work together"

Greetings from the University of Oslo Management

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Centre for Molecular Medicine Norway (NCMM) is an international biomedical research centre, with the overall objective of translating basic medical research into clinical practice. NCMM is a highly appreciated part of UiO’s strategy for life sciences, and a flagship institution for UiO. Its link as a part- nership institution with the European Molecular Biology Laboratory (EMBL) is particularly valuable.

Over the past 10 years, NCMM has demonstrated its ability to meet UiO’s expect- ations and ambitions. The centre has made substantial contributions to translational and basic molecular research, both on a local and national level. This demonstrates that NCMM has an important role when it comes to building a better understanding of diseases, in terms of detection, treatment, and prevention.

NCMM is now a well-established and important research centre, facilitating both national and international collaborations.

Over the years, the centre has grown and built on its successes to play an even more important role in the European molecular research world.

An important aspect of NCMM is its func tion as an instrument for the strategic recruitment of young group leaders.

Thanks to this, the centre has successfully recruited a number of young and talented researchers from all over the world, who have been able to establish effective and dynamic research groups. Around 70 per- cent of NCMM’s staff is international, and UiO takes great pride in hosting such an international centre.

NCMM will become an even more integral part of UiO’s strategic life science initiative (UiO:Life Science) with the planned move in 2024 into the new Life Science Building, which will be the largest and most advanced university building in Norway. It is also a pleasure that NCMM is already heavily involved in the activities of UiO:Life Science.

NCMM has a central position in two of the seven interdisciplinary research groups – the convergence environments – that UiO:Life Science appointed in spring 2017. Irep Gözen from NCMM is the only female leader of one of these environments. Dr. Gözen also received the prestigious Young Research Talent grant from The Research Council of Norway. Another young and talented researcher at NCMM, Ana Isabel Costa Cale- jo, was admitted to UiO’s new innovation programme in health-related life sciences, SPARK Norway, after the first open call.

NCMM also represents a unique collaboration between UiO, the South-Eastern Norway Regional Health Authority, and the Research Council of Norway. It has also tru- ly established itself as a national insti tution with its Associate Investigator network and other activities. It has certainly been a decade of very productive and successful

science. We recognise the importance of strengthening the interplay and coordi- nation between universities and health authorities and look forward to seeing the ownership of NCMM expand to hopefully include more of Norway’s regions.

Our investment in NCMM means that we continue to benefit from access to a national hub for strategic development in molecular and translational medicine, and also from the centre’s international networks, such as the Nordic EMBL Partnership for Molecular Medicine.

This report presents ambitious research goals and findings, and we encourage you to read it in full. It showcases excellent research and it is an uplifting and inspiring read. We know that excellent research al- most always is a prerequisite for innovation and impact, so excellence is always worth pursuing, and always worth investing in.

Svein Stølen, Rector, UiO and Per Morten Sandset, Vice Rector, UiO

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Welcome to Professor

Hartmut Luecke, Assistant Director of NCMM

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Professor Luecke is a structural biologist. Prior to joining NCMM, he was based at the University of California, Irvine, where he was Director of the Center for Biomembrane Systems and a Professor of Biochemistry.

Professor Luecke studied for his B.S. at Heidelberg University in Tiffin, Ohio, before obtaining his Ph.D. at Rice University in Houston, Texas. He joined NCMM as Assistant Director in late 2017 with an adjunct appointment at the Department of Medical Biochemistry.

What is the main focus of your research?

In a nutshell, I am a structural biologist who has a particular interest in the study of membrane proteins. I’m also interested in structure-based drug discovery; basic- ally, identifying and developing drugs that can inhibit or re-activate our targets.

What initially attracted you to NCMM?

I was particularly drawn by the prospect of working in an institute that has strong ties to medical departments at the University of Oslo, which consequently offers great opportunities for translational research.

What will you be looking for as you build your group?

My first goal is to hire skilled, motivated and enthusiastic postdocs and researchers.

One has already been hired through an H2020 MSCA IF, and I have funding for five more. My other main aim will be to work on building a national centre for structural cryo-electron microscopy at UiO.

What do you hope to accomplish in your role as Assistant Director, and what do you hope the next few years will look like at NCMM?

With the current search for a new Direc- tor of NCMM, and the upcoming external evaluation by the Research Council of Norway, the centre is at a crossroads.

My main immediate role therefore will be to mentor junior PIs, and to help with the planning of NCMM’s move to the new Life Sciences building, which is expected to happen in 2024.

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Photo: Trond Isaksen

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"NCMM wants to thank funders, stakeholders and collaborators for all the support and contributions

to the Centre over the past decade"

New Associate Investigators BiO and NCMM merger First external evaluation

First NCMM Network Meeting

Funding for second period secured Second 5 year evaluation

Looking to the future of NCMM

2016 2018

2015

2014 2017

2013 2018 and beyond

NCMM organised under Faculty of Medicine. 13 new Associate Investigators and Young Associ- ate Investigators appointed.

Taskén re-appointed as Director (2016-2020).

Merger between BiO and NCMM completed, taking total number of research groups to 11. Assistant Director Hartmut Leucke appointed.

Renewal and expansion of the Nordic EMBL Partnership Agreement (2013-2022) Suc- cess ful first external evaluation.

4th Nordic EMBL Partnership Network Meeting in Oslo.

New NCMM Director to be recruited.

NCMM will host the 9th annual Nordic EMBL Partnership Network Meeting in Oslo in September 2018. New group leader recruitments in progress for Systems Medicine and Precision Medicine. Third group leader will rotate out to a Professor position. New group to be hired.

First NCMM Network Meeting. Second Group rotates out and three new Group Leaders hired. Norway becomes official member of EATRIS-ERIC. Funding of NOR-OPENSCREEN as a national infrastructure.

Funding for second period secured (2015-19). First Group Leader rotates out to Professor position at UiO.

Sixth SAB visit. NCMM will undergo second five-year evaluation

in spring 2018.

Renewal and expansion of the Nordic EMBL Partnership Agreement in 2013 (2013-2022)

Merger between NCMM and BiO completed in 2017

Highlights from the past decade at NCMM

NCMM established First operational year Planning and approval process

New Group Leaders

Nordic EMBL Partnership Agreement signed Scientific Advisory Board established

First SAB visit

2009 2011

2008

2007 2010

2001 > 2012

NCMM established, NCMM Board appoin ted and Taskén appointed as Interim Director (2009–2010).

First operational year.

Taskén appointed as Director (2011-2015).

Centre planning and approval process. NCMM receives first visit

from the SAB.

Three group leaders hired.

Seven Associate Investi gators appointed.

Nordic EMBL Partnership Agreement signed.

Scientific Advisory Board (SAB) established.

Five Associate Investigators appointed.

Fourth and fifth Group Leaders hired.

Silke Schumacher, EMBL Director of International

Relations, at the official inauguration of NCMM First NCMM Associate Investgators appointed in 2011

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Photo: Jean Lorentzen Photo: Jean Lorentzen Photo: Lisa Balsby

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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 five-year period (2017-2022).

Dr. Anthony Mathelier is a computer scientist by background who did his PhD at the Pierre and Marie Curie University, Paris.

Mathelier was recruited from the University of British Columbia, Vancouver, Canada, 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 mechanisms by which it can be disrupted in human diseases such as cancer.

Professor Hartmut ‘Hudel’ Luecke is a structural biologist, who joined NCMM as Assis- tant Director in November 2017. He received his B.S. from Heidelberg University, Ohio and his Ph.D. in Macromolecular Crystallography from Rice University in Houston, Texas. He worked at the Stanford Synchrotron as a structural biologist before joining the faculty at the University of California, Irvine in 1996, where he was Professor of Biochemistry, Biophysics and Computer Science. He was also the founding director of the UC Irvine Center for Biomembrane Systems.

NCMM Biotechnology

Dr. Sandra Lopez-Aviles did her PhD in Barce lona followed by a postdoc in the laboratory of Frank Uhlman at the London Re- search 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 five- 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 zebrafish 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 laboratory of Professor Ben Black at the University of Pennsylva- nia, 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 Univer- sity of Technology in Gothenburg, Swe- den followed by a postdoc at Harvard-MIT Health Sciences and Technology. She started her group leader appointment at BiO in Sep- tember 2016 and her research programme focuses on the development and utilization of bionanotechnology-based methods.

Furthermore, NCMM is in the process of recruiting two new group leaders, in Sys- tems Medicine and in Precision Medicine, with appointments expected later in 2018.

"NCMM is in the pro- cess of recruit ing two new group leaders, in Systems Medicine and in Pre ci sion Medici ne, with appointments expected later in 2018"

NCMM Group Leaders

NCMM group leaders should be young, outstanding research- ers 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.

NCMM Translational Medicine

Professor Kjetil Taskén, one of 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 signalling and immunomodulation, with application in immune diseases, inflammation, and tumour immunology.

Dr. Jens Preben Morth was trained in structural biology at the EMBL Outstation in Hamburg and was recruited from Aar- hus University to NCMM in October 2010.

His research is in the area of structure and function of membrane transporters.

Morth has also started a new programme on pH regulation and structure function studies on bicarbonate transporters. His research has relevance to cardiology, neuro- biology, and kidney diseases. Morth’s appointment as group leader was evaluated in 2015 and his position was renewed for a second five-year period (2015-2020).

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 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.

From Left: Anthony Mathelier, Sandra Lopez-Aviles, Nikolina Sekulic, Camila Vicencio Esguerra, Kjetil Taskén, Irep Gözen, Judith Staerk, Jens Preben Morth, Harmut Luecke, Toni Hurtado Photo: Trond Isaksen

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Funding 2017/

Q1 2018

In addition to support from NCMM, the Taskén Group has received support from the following organisations:

Group Members

Administrative Officer

• Berit Barkley Scientific Officers

• Marianne Enger

• Martine Schrøder Research Scientists

• Einar Martin Aandahl

• Sigrid Skånland Postdoctoral Fellows

• Theresa Ahrens (joint with Staerk group)

• Deepak Balaji Thimiri Govinda Raj

• Ana I. Costa Calejo

• Stalin Chellappa

• Dinh-Toi Chu

• Andrea Cremaschi

• Aleksandra Dukic

• Håvard Foyn (from May 2017)

• Kushi Kushekar

• Anna-Mari Lone

• Kristina B. Lorvik

• Alfonso Urbanucci (from July 2017 – December 2017)

• Qian Wei (from August 2017) PhD Fellows

• Ellen Østensen (until December 2018)

• Mariaserena Giliberto (from February 2018) MSc Students

• Charlotte A. Hauge Handeland

• Marthe Jøntvedt Jørgensen (until June 2017)

• Johanne Uthus Hermansen (until June 2017)

• Norwegian Cancer Society: PGE2 and Treg regulation of anti-tumor immunity (2017-2020) and ASA clinical intervention trial in metastatic CRC.

PI BA Bjørnbeth, Co-PI KT (2017-2020)

• South-Eastern Norway Regional Health Authority (HSØ): Immune regulation of anti-tumour immunity (2017-2019)

• Norwegian Department of Health and Social Services: ASA clinical inter- vention trial in metastatic CRC. PI BA Bjørnbeth, Co-PI KT (2017-2020)

• European Commission: EU- OPENSCREEN (2017-2021)

• Private Funding: Jebsen Centre B cell malignancies (2018-2021)

• Novo Nordisk Foundation:

Regulation metabolism (2014-2018)

Key publications from the Taskén Group for 2017 and Q1 2018

Some 20 papers published in 2017/Q1 2018 include collaborative papers papers in J. Exp. Med., J.

Allergy Clin. Immunol. and Leu- kemia and key papers with mem- bers of the group as first, senior and/or corresponding author:

The Taskén Group aims to understand complex intracellular signal- ling networks and how such networks require anchoring and locali- sation through A kinase anchoring proteins (AKAPs) or other scaffold proteins. The group investigates how these signalling networks mediate hormonally regulated physiological and pathophysiologi- cal processes. In the immune system we investigate cAMP- and regulatory T cell-mediated immune-modulation with application in immune dis¬eases, inflammation and tumor immunology.

One main focus is to understand why the immune system sometimes turns off its ability to recognize and kill cells in an expanding malignant tumor. We aim to understand how tumors develop immune evasion strategies, which mechanisms operate in different cancers, and how we can perturb such immune-inhibitory signals to boost anti-tumor immunity and assist other cancer immunotherapies. We are working 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 precision oncology and hematology.

Other activities focus on the role of the cAMP second messenger system and other signal networks in the regulation of cellular function and its in¬volvement in disease mechanisms in inflammation as well as in infectious, metabolic and cardiovascular diseases.

Group achievements from the past 15 years (BiO and NCMM)

The Taskén Group has seen exponential

growth in both size and scientific outputs since it moved into the centre in 2003, initially as part of the Biotechnology Centre of Oslo (BiO) before the launch of NCMM in 2008.

Some highlights of the past 15 years include:

• Publication of 160 peer-reviewed

• papers during this time, with over 5,300 citations

• Over 500 pieces of press coverage secured

• 12 patents secured

• Over 20 industry collaborations

• 22 PhD students, 21 postdoctoral researchers and 25 MSc/BSc students trained in the group

• Over 20 clinical observation studies and five clinical intervention studies completed and/or initiated

• Protein-protein interaction studies (peptide array and Biacore), phospho proteomics and phospho-flow, regula tory T cells, chemical biology and cancer drug sensitivity screening technologies have all been adopted.

• Chelappa, S., Hugenschmidt, H., Hag- ness, M., Line, P.D., Labori, K.J., Wieds- vang, G., Taskén, K., Aandahl, E.M.

CD8+ T cells that co-express ROR t+ and T-bet are functionally impaired and expand in patients with distal bile duct cancer. J. Immunol., 2017.

• Myhrvold, I.K., Cremaschi, A., Her- mansen, J.U., Tjønnfjord, G.E., Munthe, L.A., Taskén, K., Skånland, S.S. (2018) Single cell profiling of phospho-protein levels in chronic lymphocytic leukemia.

Oncotarget, 2018.

• Dukic, A., Gerbaud, P., Thiede, B., Taskén, K.§, Pidoux, G.§ Ezrin-anchored PKA phosphorylates serine 369 and 373 on connexin 43 to enhance gap junction assembly, communication, and cell fusion.

Biochem. J., 2018 incl. cover page.

(§Corresponding authors)

Signalling Networks in Health and Disease

Kjetil T askén

Photo: Nadia Frantsen

Signalling Networks in Health and Disease

"The Taskén Group aims to translate its findings into therapeutic strate- gies and clinical practice"

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• NordForsk: (2017-2019)

• The Research Council of Norway: FriMedBio (2018-2020)

• Leeds University: Cheney Fellowship (2017-2019)

chondrial fusion and fission machinery are seen in the range of diseases mentioned above (Archer, 2013; Sharp and Archer, 2015). Re- cently, tumors were found to reprogram mitochondrial dynamics in neurons (Caino et al., 2016). The Membrane-associated RING-CH protein 5 (MARCH-5) is an outer mitochondrial membrane-embedded E3 ubiquitin-protein ligase thought to target components of the mitochondrial fusion/fission machinery directly. (Bauer et al., 2017). However, the exact role of MARCH 5 within the fusion or fission machinery, its regulation and its substrates are still controversially discussed.

Group Members

Principal Engineer

• Bojana Sredic Postdoctoral Fellows

• Johannes Bauer

• Harmonie Perdreau-Dahl

• Saranya Subramani PhD Fellows

• Lisa Gerner (until February 2017)

• Julia Weikum (from April 2017)

• Nils Valentin (Shared with Sandip Kanse) MSc Students

• Annika Kratzel (Erasmus Student, April 2017 – July 2017)

• Line Jægerum (Guest student, August 2017 – December 2017)

• Maria Zajaczkowska (Guest student, September 2017 – December 2017)

"The Morth Group focus- es on the structure and function of membrane proteins, and their inter- action with lipids in the biological membrane"

Funding 2017/

Q1 2018

In addition to support from NCMM, the Taskén Group has received support from the following organisations:

Membrane Transport Group

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Publications from the Morth Group 2017:

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 proteins and interaction partners of interest. Further- more, X-ray crystallography and several biophysical methods to obtain structural information and biochemical techniques, including activity assays and fluorescence spectroscopic measurements, are also used.

The magnesium transport system in bacteria, fungi, and plants

Active magnesium uptake through the bacterial transporter (MgtA) exists in a broad range of bacterial species, including many of the bacteria residing in the intestine, such as the E. coli (so-called proteobacteria) (Maguire, 2006). Many pathogenic microbes also try to make their way through our intestines, trying to avoid detection, before entering the human bloodstream. Recently MgtA expression has been established as a key component of intrin-

Nielsen, M. S., Oxvig, C., Morth, J. P., Matchkov, V. V.,Aalkjaer, C., Bundgaard, H., and Jensen, H. K. (2017) Loss-of-acti- vi ty-mutation in the cardiac chloride-bi- car bo nate exchanger AE3 causes short QT syndrome. Nat Commun 8,1696

• Chollet, M. E., Andersen, E., Skarpen, E., Myklebust, C. F., Koehler, C., Morth, J.

P.,Chuansumrit, A., Pinotti, M., Bernardi, F., Thiede, B., Sandset, P. M., and Skret- ting, G. (2017) Factor VII deficiency: Un- veiling the cellular and molecular mechan- isms underlying three model alter ations of

the enzyme catalytic domain. Biochim Biophys Acta 1864, 660-667

• Bauer, J., Bakke, O., and Morth, J. P. (2017) Overview of the membrane-associated RING-CH (MARCH) E3 ligase family.

N Biotechnol 38, 7-15

• Alvadia, C. M., Sommer, T., Bjerregaard- Ander sen, K., Damkier, H. H., Montrasio, M., Aalkjaer, C., and Morth, J. P. (2017) The crystal structure of the regulatory do- main of the human sodium-driven chloride/

bi carbonate exchanger. Sci Rep 7, 12131

• Uribe, L., Diezemann, G., Gauss, J., Morth, J. P., and Cascella, M. (2017) Structural Origin of Metal Specificity in Isatin Hydrolase from Labrenzia aggre- gata Investigated by Computer Simula- tions. Chemistry

• Thorsen, K., Dam, V. S., Kjaer-Sorensen, K., Pedersen, L. N., Skeberdis, V. A., Jurevicius, J., Treinys, R., Petersen, I.,

Membrane Transport Group

sic ribosome instability (Chadani et al., 2017) and nitro-oxidative stress (Bourret et al., 2017).

We expect that our efforts to understand the bacterial MgtA and why some plants also have homologs of a naturally occurring magnesium transporter (P3B ATPase) could lead to the development of poten tial future agricultural applications. Recent work describes the first direct evidence that cardiolipin is co-local- ized with MgtA in the E. coli membrane and can activate MgtA in vitro. Cardiolipin thus functions as a magnesium chaperone for MgtA. Our data presents further evidence that free magnesium is the transported ion by MgtA, indicating that magnesium recog- nition likely takes place before magnesium enters the ion-binding site. At elevated magnesium concentrations allosteric substrate inhibition by free magnesium is observed and thus indicates that MgtA has receptor- like properties (Subramani et al., 2016) Structural and functional characteri sation of Bicarbonate transporters

The acid/base balance and cellular pH regulation is highly dependent on the bicarbo-

nate transporters residing in the plasma membrane. These transporters are divided into three major classes. We have established the first direct link between the cyto plasmic domain of the electrogenic, Na+, HCO3- co- transporters 2 (NCBe2) (Alvadia et al., 2017) and have co-authored an extensive study spanning from the clinic to structural biology, describing the only known mutant found in the Na+-independent Cl-/

HCO3- exchanger 3 (AE3), leading to short QT syndrome (Thorsen et al., 2017).

Trafficking and biochemical and structure characterisation of MARCH 5)

Defective mitochondrial function has been associated with severe conditions, such as cardiovascular and neurodegenerative diseases, metabolic disorders, and cancer. There are several levels of regulation linked to mitochondrial function. However, mitochondrial dynamics are often associated with the finely tuned fusion and fission events happening at mitochondrial membranes (Archer, 2013;

Kasahara and Scorrano, 2014; Schrepfer and Scorrano, 2016). Abnormalities in the mito-

J. Preben Morth

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Funding 2017/

Q1 2018

In addition to support from NCMM, the Hurtado Group received funding from the following organisations:

addition, we have identified proteins not present within the list of ER-interacting proteins. Among these Tamoxifen ER-independent targets we have identified the protein SKIP, which is an important modulator of TGF-beta/Smad signalling.

Considering the intricate roles of these major signalling pathways in mammary epithelial cells biology and tumorigenesis, and their extensive interactions, we are currently investigating how Tamoxifen regulates the crosstalk between these pathways.

Group Members

Postdoctoral Fellows

• Sachin K. Singh (until December 2017)

• Anne Marthe Fosdahl

• Shixiong Wang (from January 2018) PhD Fellow

• Shixiong Wang (until December 2017) Head Engineers

• Siv Gilfillan (until June 2017)

• Neus Daviu (July 2017-December 2017) MSc Students

• Elvia Valentini (Erasmus student)

• Madhuri Manivannan (Erasmus student)

• Neus Daviu (until April 2017)

• Research Council of Norway:

Young Talent Grant (2016-2020)

• South-Eastern Norway Regional Health Authority (HSØ):

(2016-2019)

"The main interest of the Hurtado Group is to understand the mechan- ism of hormone resist- ance in breast cancer"

Breast Cancer Group –

Publications from the Hurtado Group 2017

The main aim of the Hurtado Group is to understand mechanisms of hormone resistance in breast cancer. We are interested in determining how the estrogen antagonist Tamoxifen contributes to the inhibition of breast cancer progression. In addition to our breast cancer research, our team has an ongoing collaboration with the group of Prof. Krakstad at the University of Bergen. Here we aim to elucidate mechanisms of resistance to anti-HER2 therapies in endometrial cancer. We also investigate the interplay of the transcription factor FOXA1 and the receptor tyrosine kinase HER2. The focus of our research can therefore be summarised in two main projects: (1) Elucidating cell-signalling pathways controlling FOXA1 functions in breast cancer and endometrial cancer; (2) Searching for novel mechanisms of action for the anti-estrogen drug Tamoxifen.

Elucidating cell-signalling pathways controlling FOXA1 functions in breast cancer

Resistance to endocrine therapy is complex, heterogeneous and may differ from patient to patient. The majority of clinical trials thus far have focused on combining or alter- nating endocrine therapy agents, or inter- calating targeted therapies against kinase inhibitors such as CDK, PI3KAKT-mTOR, EGFR or HER2. We have seen that FOXA1 is an important mediator of HER2/HER3 signalling (Gilfillan, in resubmission), and decided to study how other pathways with implications in cell proliferation could regulate its function. Our final goal is to better understand the mechanisms that lead to resistance to current treatments that are mediated by FOXA1. To test whether other kinases impact FOXA1 function, we have also carried out a drug screening using a

selected subset of kinases and phosphatases with known implications in breast cancer.

Searching for novel mechanisms of action for the anti-ER drug Tamoxifen The precise mechanism of action of Tamoxi- fen is still not completely understood. In our studies, we have aimed to identify targets relevant for Tamoxifen repressive action.

We used a chemical proteomics approach, which allows the identification of drug targets. Next, we performed proteomics to identify novel Tamoxifen-interacting proteins and compared these to known protein targets of ER-tamoxifen. Import- antly, this targeted proteomics approach revealed that 50% of the Tamoxifen-biotin pulled down proteins were also identified within the ER-Tamoxifen pull down, which confirmed the suitability of this method to identify Tamoxifen-interacting proteins. In

• Fleischer, Thomas; Tekpli, Xavier;

Mathelier, Anthony; Wang, Shixiong;

Nebdal, Daniel J.H.; Dhakal, Hari Pras- ad; Sahlberg, Kristine Kleivi; Schlicht- ing, Ellen; Børresen-Dale, Anne-Lise;

Borgen, Elin; Naume, Bjørn; Eskeland, Ragnhild; Frigessi, Arnoldo; Tost, Jörg;

Rodriguez, Antoni Hurtado; Kristensen, Vessela N. DNA methylation at enhancers identifies distinct breast cancer lineages.

Nature Communications 2017 ;Volum 8.(1379)

• Halle, Mari Kyllesø; Tangen, Ingvild Løberg; Berg, Hege Fredriksen; Hoivik, Erling A; Mauland, Karen Klepsland;

Kusonmano, Kanthida; Berg, Anna;

Rodriguez, Antoni Hurtado; Kalland, Karl; Øyan, Anne Margrete; Stefans- son, Ingunn; Vintermyr, Olav Karsten;

Werner, Henrica Maria Johanna;

Haldorsen, Ingfrid S.; Trovik, Jone;

Salvesen, Helga; Krakstad, Camilla.

HER2 expression patterns in paired primary and metastatic endometrial cancer lesions. British Journal of Cancer 2017 ;Volum 118. s.378-387

Breast Cancer Group

Antoni Hurtado

(12)

Group Members

• Kirsti E. Præsteng (until December 2017)

Chronic lymphocytic leukemia (CLL) is a common hematological cancer in adults and is characterised by clonal B cell expansion. Over the past year, the group asses- sed cell cycle defects in CLL, and found that a significant number 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 (Rogne et al, 2018).

Lamin proteins and haematopoiesis The nuclear lamina is composed of lamins, intermediate filaments that have been impli cated in regulation of gene expression by tethering chromatin regions to the nuclear periphery through so called lamin-associated domains (LADs). Using CD34+ progenitor and mature blood cell types, the group has generated a high resolution map of genomic regions that dynamically and constantly reside within LaminB1-LADs and have shown that LMNB1 has a differentiation-specific LAD signature in the hematopoietic tissue. In CD34+ cells and monocytes, facultative and constitutive LADs are silent for gene expression, as generally described for LADs. Strikingly, in lymphoid cell types, LADs contain tran- scriptionally active regions correlating with a distinct enrichment of epigenetic marks around transcription start sites. Currently, the group investigates the impact of this finding on blood cell development.

"The Staerk Group aims to under stand how mole- cular processes control haematopoiesis"

Rogne Marie, Svaerd Oksa- na, Madsen- Østerbye Julia, Hashim Adnan, Tjønnford Geir E, Staerk Judith.

Cytokinesis arrest and multiple centrosomes in B cell chronic lymphocytic leukemia. Journal of Cellular and Molecular Medicine (2018)

Stem Cell Group

–

The Staerk Group focuses on deciphering molecular processes that govern hematopoietic specification, hematopoietic stem cell (HSC) renewal and differentiation, as well as formation of mature blood cells. Understanding the mechanisms governing blood development is important, both to decipher the underlying molecular events that drive lifelong formation of blood cells, and to identify pathways that are dysregulated in blood disorders.

The overall goals of the group’s research are to: i) functionally characterize epigenetic and genetic factors and signalling pathways during hematopoietic development, and ii) decipher the mechanism by which the nuclear lamina modulates hematopoietic development. To achieve these goals, we use human pluripotent stem cells and in vitro differentiation assays along with primary samples. We then combine these assays with genetic and genomic approaches. In- sight obtained from our research projects will help to identify factors needed for effi- cient blood cell differentiation, and how this differentiation is affected in disease.

Stem Cell Group

Epigenetic dynamics during blood cell differentiation DNA methylation and 5 hydroxymethylation in pluripotency and human development

We aim to decipher how epigenetic changes, transcriptional networks and metabolic changes affect pluripotency and human development. How do epigenetic modifiers such as TET and Dnmt enzymes interact with non-coding RNA (nc-RNAs), which nc-RNA networks are required for pluripotency and differentiation of human embryonic stem cells (ESCs) and how does deficiency in epigenetic enzymes affect the availability of metabolic substrates?

DNMT3A and DNMT3B are two important epigenetic factors that catalyze de novo methy lation of DNA, and Ten-eleven-trans- location (TET) enzymes are crucial for the demethylation process and generation of 5hmC. In order to differentiate properly, ESCs have to undergo precisely coordinated epigenetic and metabolic changes. It has been shown that metabolites can alter the activity of epigenetic enzymes and vice-versa and epigenetic modifications can regulate the ex-

pression of metabolic enzymes. Mechanisms and factors taking part in these processes are still not known. We inactivated TET1 and DNMT3s in human ESCs, and are currently assessing changes in global DNA methylation and 5hmC levels and distribution using mass spectrometry, as well as oxidative bisulfite sequencing. Moreover, we study the influence of these changes on gene expression and availability of key metabolites.

Projects with translational impact Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders, characterised by impaired haematopoiesis and a predisposition to developing acute myeloid leukaemia (AML). The underlying cause for MDS is not completely understood. The group is using primary patient samples as well as patient-derived induced pluripotent stem cells (iPSCs) to analyse the potential of these iPSC to differentiate into hematopoietic progenitors, and to screen transcription factor and miRNA libraries to identify candidate genes to reverse the potential block in in vitro blood cell differentiation.

Judith Staerk

Publications from the Staerk Group 2017 & Q1 2018

• Cieslar-Pobuda, Artur; Knoflach, Viktoria; Ringh, Mikael V.; Stark, Joachim; Likus, Wirginia; Siemiano - wicz, Krzysztof; Ghavami, Saeid;

Hudecki, Andrzej; Green, Jason L.; os, Marek J. Transdifferentiation and repro- gramming: Overview of the processes, their similarities and differences. BBA – Molecular Cell Research 2017;Volum 1864.(7) s.1359-1369

Funding 2017 & Q1 2018

In addition to support from NCMM, the Staerk Group has received fund- ing from the following organisations:

Young Talent Grant (2015-2019) and Stem Cell Grant (2014-2017)

• Scientia Fellows: EU co-fund programme (2015-2018)

• The Norwegian Stem Cell Centre (UiO): Three-year postdoc (2014-2017)

• University of Oslo: Postdoctoral Fellowship (2014-2017)

• Theresa Ahrens (joint with Taskén Group)

• Safak Caglayan

• Artur Cieslar-Pobuda

• Adnan Hashim

• Marie Rogne (until December 2017)

PhD Fellows

• Julia-Kristina Madsen-Østerbye (until December 2017)

• Oksana Svärd (until May 2017)

(13)

Funding 2017

& Q1 2018

In addition to support from NCMM, the Mathelier Group was awarded an NCMM collaborative grant with the group of NCMM Associate Investigator Hege Russnes (Oslo University Hospital).

Group Members

• Aziz Khan

• Jaime Castro Mondragón (from October 2017)

PhD Fellow

• Marius Gheorghe MSc Students

• Kübra Altinel (October 2017- June 2018)

• Eleftherios Pavlos

(Erasmus student, until March 2017)

• Victor Laigle (March – August 2017)

• Arnaud Stigliani (September – December 2017)

Frigessi, J. Tost, A. Hurtado, and V.N.

Krist ensen. DNA methylation at enhancers identifies distinct breast cancer lineages. Nature Communications, 2017. doi:10.1038/s41467-017-00510-x

• J. Chèneby, M. Gheorghe, M. Artufel, A.

Mathelier, and B. Ballester. ReMap 2018:

an updated atlas of regulatory regions from an integrative analysis of DNA-bind- ing ChIP-seq experiments. Nucleic Acids Research, 2017. doi:10.1093/nar/gkx1092

• D. de Rie, I. Abugessaisa, …, A.

Mathe lier, …, M.J.L. de Hoon (~70 authors from the FANTOM5 Con- sortium). An integrated expression atlas of miRNAs and their promoters in human and mouse. Nature Biotech- nology, 2017. doi:10.1038/nbt.3947

• A. Khan and A. Mathelier. Intervene:

a tool for intersection and visuali- zation of multiple gene or genomic region sets. BMC Bioinformatics, 2017.

doi:10.1186/s12859-017-1708-7

"The Mathelier Group works to build a better understanding of how gene expression is regu- lated, and how it can be disrupted in disea ses like cancers"

Computational Biology

and Gene Regulation –

Publications from the Math- elier Group 2017 & Q1 2018

* co-first authors, + co-corresponding authors

• D. Sugiaman-Trapman, M. Vitezic, E.-M.

Jouhilahti, A. Mathelier, G. Lauter, S.

Misra, C.O. Daub, J. Kere+, and P. Swobo- da+. Characterization of the human RFX transcription factor family by regulatory

The Mathelier Group develops and assesses computational methods to analyse the genomic sequence (DNA). The goal of the group is to create the next generation of cutting-edge algorithms and open computational biology software that can be applied to real-life biological problems.

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 Mathelier Group tries to predict which mutations in the non-coding portion of the human genome (i.e. not coding for proteins) are causal for diseases.

As successful computational biology research relies on high quality data, of which the group has a strong understanding, work is currently focused on combining large amounts of experimental data with in house computational models to identify the binding sites of transcription factors (TFs); key proteins binding to the switches that control when, where, and to what extent genes are

transcribed. It has been shown that mutations within TF binding sites can alter gene expression, triggering human diseases such as cancer. Current work will provide the group with a critical map for further studies of where TFs bind in the human genome.

The group next plans to combine whole genome sequencing with gene expression data from cancer patient samples with its high-quality regulatory map. This will provide new insights into the predictions of the impact of the mutations dysregulating gene expression and contributing to cancers.

The group also aims to provide the research community with useful tools to facilitate their research. As an example, they have recently developed a computational tool called Intervene, which provides an easy way to compute and visualise intersections of multiple genomic regions and list sets. The tool was developed and designed to meet the needs of both computer scientists and biologists to help the analysis and interpre- tation of genomic region set intersections.

and target gene analysis. BMC Genom- ics, 2018. doi:10.1186/s12864-018-4564-6

• A. Khan and A. Mathelier. JASPAR REST- ful API: accessing JASPAR data from any programming language. Bioinformatics, 2017. doi:10.1093/bioinformatics/btx804.

• A. Khan*, O. Fornes*, A. Stigliani*, M.

Gheorghe, J.A. Castro-Mondragòn, R.

van der Lee, A. Bessy, J. Chèneby, S.R.

Kulkarni, G. Tan, D. Baranasic, D.J.

Arenillas, A. Sandelin+, K. Vandepoele,

B. Lenhard+, B. Ballester, W.W. Was- serman+, F. Parcy, and A. Mathelier+.

JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework. Nucleic Ac- ids Research, 2017. doi:10.1093/nar/gkx1126

• T. Fleischer*, X. Tekpli*, A. Mathelier, S. Wang, D. Nebdal, H.P. Dhakal, K.

Kleivi Sahlberg, E. Schlichting, Oslo Breast Cancer Research Consortium (OSBREAC), A.-L. Børresen-Dale, E.

Borgen, B. Naume, R. Eskeland, A.

Computational Biology and Gene Regulation

Anthony Mathelier

(14)

Funding 2017

& Q1 2018

In addition to support from NCMM, the Luecke Group has received funding from the following organisations:

We use a multidisciplinary approach that involves crystallography, nuclear magnet- ic resonance, cryo electron microscopy and computational techniques to obtain structural and mechanistic insights on numerous systems.

One of our projects focuses on annex- ins that constitute a family of proteins that interact with phospholipid bilayers in a Ca2+-dependent manner. Mediating membrane aggregation and fusion, an- nexins play important roles in endo- and exocyto sis, actin polymerization, inflam- matory response, cancer metastasis, and the gene ration of plasmin. Structural studies of ann exins have been essential for understanding their properties and interactions with binding partners at the atomic level. We are now characterizing several lead compounds that modulate annexin-mediated polymerization of actin, some of which have demonstrated anti-angiogenic activity.

Group Members

Research Scientist

• Eva Cunha (from April 2018)

The Luecke lab at NCMM is currently in its establishment phase. Four postdoctoral fellows, a PhD fellow, M.Sc/MD students and a technician are expected to be recruited in 2018.

• The Research Council of Norway: FRIMEDBIO grant

• Worldwide Cancer Research

• H2020 MSCA IF (Dr. Eva Cunha)

"The Luecke Group aims to better understand the structure and function of integral membrane prote ins.

We also aim to identify and develop drugs that inhibit or re-activate our targets"

Structural Biology and Drug Discovery –

Summary of current research focus:

Hartmut Luecke was recruited to NCMM in November 2017, and is currently in the process of establishing his research group. He is also spearheading an effort to bring single-particle cryo-electron microscopy to Norway. The group will focus on two main areas of research:

Structure-function studies of integral membrane proteins

Though most genomes contain 20-30% of membrane proteins, to date we only know the atomic structures of just over 2,000 membrane proteins (vs. over 140,000 for soluble proteins). Our approach has been to employ and refine a host of specialized crystallization methods, and more recently we have begun cryo electron microscopy studies of the complex of a membrane protein with a large soluble enzyme.

Central to more than half of all human cancers is the tumor suppressor protein p53. A subset of five single-site mutations in the DNA-binding domain of p53 is found in the vast majority of these cancers (top three are ovarian, lung and colorectal). The Luecke group aims to identify compounds that restore the function of mutant p53, using structural studies.

Infection of the gastric mucosa by Helico- bacter pylori affects about half the world’s population and is the primary cause of

gastritis, peptic ulcer disease and gastric cancer. Gastric colonization by H. pylori depends on the expression of a proton-gated urea channel and a cytoplasmic urease unique to this pathogen. We have determined the structure of this channel which is essential for H. pylori survival in the low-pH medium of the stomach and is thus an attractive cancer target. More recently we determined the structure of 1.1 MDa urease by cryo EM to 3.2 Å resolution.

We have also identified compounds that inhibit the channel or the urease at sub- micromolar concentrations. Thus, the second general area of our research interest is structure-based drug discovery.

Structure-based drug discovery

Structural knowledge is fundamental for understanding the underlying mechanisms involved in cancer onset and proliferation.

This therefore aids in the identification and the development of new and more effective drugs.

• The acid-gated urea channel from Helicobacter pylori, a bacterium that is estimated to chronically infect about half of all humans, leading to ulcers and stomach cancer

• Annexin A2, metastasin (S100A4) and p11 (S100A10) are cancer and cardiovascular targets

• Reactivation of cancer mutants of p53, the well-known tumor suppressor

• Terminal uridylyl transferases involved in RNA-editing in trypa no- somatids Inosine-5'-monophos - phate dehydrogenase from the parasites P. falci parum and T. foetus

• Nuclear receptors, in particular PPAR-alpha (obesity)

Structural Biology and Drug Discovery

Hartmut Luecke

(15)

Funding 2017

& Q1 2018

In addition to support from NCMM, the Lopez-Aviles Group has received funding from the following organisations:

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 mechanisms that lead to this control, speci- fi cally 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.

Group Members

Engineer

• Mari Nyquist-Andersen Researcher

• Ruth Martin Postdoctoral Fellows

• Nathalia Chica-Balaguera

• Marina Portantier PhD Fellow

• Vilte Stonyte (from June 2017) MSc Students

• Marcos Veloso-Carril (from October 2017)

• Freya Rosenberg (from October 2017)

• The Norwegian Cancer Society (2016-2017)

• The Research Council of Norway: Young Talent Grant (2016-2019)

• Scientia Fellows: EU co-fund programme (2016-2018)

"The Lopez-Aviles Group aims to build a better understanding of the cell cycle, using fission yeast as a model organism"

Cell Cycle Regulations Group

–

Publications from the Lopez-Aviles Group 2017

The Lopez-Aviles group's main research interest focuses on under- standing the implications of regulated phosphatase activity during cell-cycle progression, using the fission yeast Schizosaccharomyces pombe as a model organism.

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 spati ally regulated for an ordered cell cycle progression. We, however, are interested in the role of the CDK (Cyclin-Dependent Kinases) opposing activity, that is, protein phosphatases. We focus our efforts on study ing the processes regulated by protein phosphatases that are relevant to cell cycle progression. We believe these studies could help us to better understand the cell cycle.

More specifically, our research includes:

Regulation of mitotic progression by protein phosphatases, par ticu larly type-2A phosphatases

We examine the role of phosphatase activity in the ordering of Cdk-substrates dephosphorylation, as well as in the en- gagement of feedback loops that lead to the irreversible inactivation of Cdk complexes during mitotic exit. We also investigate

how phosphatase activity influences the behaviour of cells during a sustained mitotic arrest. Since cells arrested in mitosis for long periods eventually undergo pro- grammed cell death, understanding 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 con- necting the activities of the two TOR complexes, TORC1 and TORC2. This becomes particularly relevant during nutritional deprivation, a signal 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 involve- ment of PP2A in the regulation of protein translation, as well as in the regulation of epigenetic marks and gene transcription.

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

• Martin, R and Lopez-Aviles, Express yourself: How PP2A helps TORC1 talk to TORC2. Current Genetics (2017) Jun 22

• Rothe, C., Rødland, G. E., Anda, S., Stonyte V., Boye, E., Lopez-Aviles, S.

and Grallert, B. (2017) A checkpoint- independent mechanism delays entry into mitosis. Journal of Cell Science (2017) 130(23):4028-4037

Cell Cycle Regulations Group

Sandra Lopez-A viles

(16)

Chemical

Neuroscience Group

–

Funding 2017

& Q1 2018

In addition to support from NCMM, the Esguerra Group has received additional funding from:

The Esguerra Group focuses on exploring the fundamental mechan isms underlying brain function in health and disease.

Research focus

Using a combination of genetic and chemical approaches in zebrafish, the group seeks to elucidate the mechanisms of seizure generation, epileptogenesis, and treatment resistance through probing the function of novel disease-associated gene variants involved in the etiology of pharmacoresistant epilepsies and, more recently, neuropsychiatric diseases such as schizophrenia.

The group uses genetically engineered zebrafish mutants and transgenic reporter lines, as well as pharmacologically-induced disease models. These models and will serve as valuable tools towards understanding the development, function, and diseases of the brain.

Aims:

Generate novel zebrafish epilepsy and schizophrenia models

Functionally confirm disease- causa tive gene variants in vivo (genotype-phenotype correlation) Identify bioactive small molecules with potential utility as antiepileptic and antipsychotic drug leads and pharmacological tools Elucidate mechanisms of action of identified small molecules

Group Members

Head Technician

• Rønnaug Steen Kolve Research Technicians

• Daniel James Wrobleski

• Nelson Thapelo Mathabela (November 2017 – June 2018) Postdoctoral Fellows

• Ettore Tiraboschi

• David Ramonet-Jimenez

• Kinga Aurelie Gawel (from January 2018) PhD Student

• Nancy Saana Banono (from August 2017) MSc Students

• Gezime Seferi (from February 2017)

• Anna Thao Nguyen (until May 2017) Erasmus Student

• Sarah Heintz (from April 2018) Intern

• Rens Wisse (until January 2018) Job student

• Evan Michael Vallenari (from September 2017)

• EU ERA-NET Neuron: "SNAREopa- thies: Mechanisms of neuropsychiatric genetic diseases of the SNARE complex: towards therapeutic intervention" (2018-2021)

• German Research Council: "Mechan- isms of Epileptogenesis in Genetic Epilepsies" (2018-2020)

Digibrain (2017-2020)

• Marie Sklodowska-Curie Actions Post-Doctoral Fellowship (2019-2020)

• Polish Research Council Post-Doctoral Fellowship (2018)

• Scientia Post-Doctoral Fellowship:

EU co-fund Programme (2016-2018)

Chemical Neuroscience Group

Camila V icencio Esguerra

"The Esguerra Group aims to build a better understanding of the development, function, and diseases of the brain"

1 2

3

4

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Foto: Navnesen

Structural Biology and Chromatin Group

–

Funding 2017 & Q1 2018 Publications from the Sekulic Group 2017

In addition to support from NCMM, the Sekulic Group has received support from the following organisation:

• The Research Council

of Norway: Young Talent Grant (2017-202)

The Sekulic Group uses modern biophysical methods in combi- nation with structural methods and cell biology to answer important questions in the filed of chromatin biology.

The group is particularly interested in the centromere, the part of the chromosome that governs chromosome segregation during cell division. During mitosis, duplicated chromosomes are held together in a special region of the chromosome, which is called the centromere. At the top of the centromere, a protein megacomplex, the kinetochore, forms to connect duplicated chromosomes to microtubules emanating from opposite poles of the dividing cell. Only when all the chromosomes attach correctly to microtubules, are the sister chromatids then separated, travelling to the poles of the dividing cell.

Mistakes leading to inaccurate chromosome segregation during cell division can often either be catastrophic, or can result in an- euploidy, which is associated with cancer.

The group is interested in understanding the molecular basis of centromere architec- ture, how the centromere recruits enzymes with important roles during mitosis and, finally, what are the molecular mechanisms behind the (de)activation of key mitoic enzymes (kinases and phosphatases).

Our research will also help with further understanding the basic mechanisms that underpin how genetic information is maintained through division and duplication, as well as the processes that lead to cancer.

These findings will hopefully provide possible new avenues for fighting the disease.

The Sekulic Group is equipped with state- of-the-art instrumentation for structural biology and mass spectroscopy. The group also collaborates closely with experts in yeast genetics and cell cycle regulation.

Group Members

• Stine Malene Hansen Wøien Researcher

• Dario Segura-Peña Postdoctoral Fellow

• Ahmad Ali Ahmad

• Guo LY, Allu PK, Zandarashvili L, McK- inley KL, Sekulic N, Dawicki-McKenna JM, Fachinetti D, Logsdon GA, Jami- olkowski RM, Cleveland DW, Chee- seman IM, Black BE. Centromeres are maintained by fastening CENP-A to DNA and directing an arginine anchor-de- pendent nucleosome transition. Nat Commun. 2017 Jun 9;8:15775

Structural Biology and Chromatin Group

Nikolina Sekulic

"The Sekulic Group is

inter ested in understanding the molecular mechanisms that ensure genomic stabi- lity during mitosis"

Nechemia-Arbely Y, Fachinetti D, Miga KH, Sekulic N, Soni GV, Kim DH, Wong AK, Lee AY, Nguyen K, Dekker C, Ren B, Black BE, Cleve- land DW. Human centromeric CENP-A chromatin is a homotypic, octameric nucleosome at all cell cycle points. J Cell Biol. 2017 Mar 6;216(3):607-621. doi:

10.1083/jcb.201608083. Epub 2017 Feb 24

From disease mechanisms to clinical practice