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SCIENTIFIC REPORT 2013 Cruk.Org SCIENTIFIC Cover Image Graduate Student Loic Fort from Laura Machesky’S Group SCIENTIFIC REPORT 2013 cruk.org SCIENTIFIC Cover image Graduate student Loic Fort from Laura Machesky’s group. REPORT 2013 BEATSON INSTITUTE CONTENTS SECTION 1 ADVANCED TECHNOLOGIES INTRODUCTION 04 Kurt Anderson 48 RESEARCH HIGHLIGHTS 06 Beatson Advanced Imaging Resource (BAIR) BACKGROUND 10 Gabriela Kalna 49 Bioinformatics and Computational Biology CANCER RESEARCH UK BEATSON INSTITUTE Gillian Mackay 50 Metabolomics REGULATION OF CANCER CELL GROWTH METABOLISM AND SURVIVAL Nick Morrice 51 Eyal Gottlieb 12 Proteomics and Mass Spectrometry Apoptosis and Tumour Metabolism Emma Shanks 52 Danny Huang 14 RNAi Screening Ubiquitin Signalling Karen Blyth 53 Hing Leung 16 Transgenic Models of Cancer Prostate Cancer Biology Douglas Strathdee 54 Kevin Ryan 18 Transgenic Technology Tumour Cell Death Karen Vousden 20 SECTION 2 Tumour Suppression BEATSON ASSOCIATES Peter D. Adams 56 REGULATION OF CANCER CELL INVASION Epigenetics of Cancer and Ageing AND METASTASIS Daniel J. Murphy 58 Kurt Anderson 24 Oncogene-Induced Vulnerabilities Tumour Cell Migration Stephen Tait 60 Jeff Evans 26 Mitochondria and Cell Death Translational Cancer Therapeutics Robert Insall 28 UNIVERSITY OF GLASGOW Cell Migration and Chemotaxis Jeff Evans 64 Laura Machesky 30 Institute of Cancer Sciences Migration, Invasion and Metastasis Jim Norman 32 SECTION 3 Integrin Cell Biology RESEARCH FACILITIES 72 The Beatson Institute for Cancer Michael Olson 34 PUBLICATIONS 76 Research building Molecular Cell Biology CONFERENCES AND WORKSHOPS 90 Owen Sansom 36 SEMINARS 92 Colorectal Cancer and Wnt Signalling STUDENTSHIPS AND POSTDOCTORAL 94 FELLOWSHIPS Marcos Vidal 38 ADMINISTRATION 95 Drosophila Approaches to Cancer THANKS FOR SUPPORTING US 96 Sara Zanivan 40 PATRONS AND BOARD OF GOVERNORS 99 Vascular Proteomics CONTACT DETAILS 100 DRUG DISCOVERY Martin Drysdale 44 Drug Discovery Programme 2 SCIENTIFIC REPORT 2013 CANCER RESEARCH UK BEATSON INSTITUTE 3 INTRODUCTION Members of the Beatson Cancer This year was an extremely important and busy one for us with Metabolism Research Unit at quinquennial reviews of both the Institute and the Drug work (CaMeRU) Discovery Programme being held in June. We also took a lead role in the renewal of the CRUK Glasgow Centre. Our Institute review was a great success and a tumour types and we were delighted to be Professor Karen Vousden fantastic endorsement of everyone’s hard work awarded a substantial increase in the funding CBE, FRS, FRSE, FMedSci over the past few years. The review panel was available to support these areas. The Centre also Director of The Beatson very positive about our progress to date and had the pleasure of welcoming Stan Kaye as Institute for Cancer Research future plans – especially our move to develop Chair of its Governance Board. Stan, who has cancer metabolism. An increasing number of worked at the Institute of Cancer Research in our research groups are doing excellent work in London for many years, brings considerable this area as can be seen from our research expertise to this role as well as extensive highlights, which include a number of knowledge of cancer research in Glasgow from metabolism-focused papers. We are also his time here as Chair of Medical Oncology. putting considerable effort into establishing our Cancer Metabolism Research Unit (CaMeRU), This year saw the departure of a long-standing headed by Eyal Gottlieb, and we have been member of the Institute David Gillespie, who actively engaged in recruiting the people and secured a position at the University of Tenerife building the resources in support of this. Our where he will continue his research programme first group leader appointment will be Jurre on checkpoints and cell cycle control. Dave Kamphorst, whose expertise is in lipid joined the Beatson in 1989 and made important metabolism and who will join us as a Beatson contributions to the work of the Institute as well departing postdocs winning fellowships and coming years. Our students had the great Associate in early 2014. as acting as a mentor and overseeing our taking up independent group leader positions pleasure of playing host to Sir Paul Nurse who postdoctoral training programme. We wish elsewhere, including Celia Berkers (Utrecht), visited this year in his role as President of the The review of the Drug Discovery Programme, Dave all the best in sunnier climes. Julia Cordero (Glasgow), Jason King Royal Society. the first since its inception, was also (Sheffield),Patricia Muller (MRC Toxicology encouraging about what the unit has achieved We also said farewell to our Laboratory Manager Unit, Leicester) and Tobias Zech (Liverpool). Finally, as every year we would like to extend our so far and its future plans. There is a growing Robert MacFarlane, who retired from the heartfelt thanks to all the donors and supporters integration between the work of the unit and Institute at the end of August after 42 years of We also saw a large number of students whose generosity makes our work possible. the rest of the Institute, an initiative that is being service. His contribution to the Institute was successfully graduate this year and we look led by the head of the DDP, Martin Drysdale. extraordinary and we wish him the very best for forward to seeing their careers develop in the his retirement. Meanwhile, Laura Bence joined We were also co-applicants, along with us to take on this key role. colleagues from the Institute of Cancer Sciences at the University of Glasgow, on a I was delighted to be elected to the American successful application to renew our CRUK Association for the Advancement of Science, Centre status. The new award includes an while one of our junior group leaders Marcos important training component in support of Vidal was recognised by being elected to the students and clinical fellows but particularly Young Academy of the Royal Society of focuses on providing infrastructure in the areas Edinburgh. of co-clinical trials, informatics, biomarkers, biospecimens and functional screens. The goal The Institute review panel highlighted the is to provide a platform of technical expertise excellent training environment we provide for and technological capabilities to support students and postdoctoral scientists and this members of the Centre across all disciplines and was reflected again this year with several of our 4 SCIENTIFIC REPORT 2013 CANCER RESEARCH UK BEATSON INSTITUTE INTRODUCTION 5 RESEARCH HIGHLIGHTS This section features some of the key research findings It is known that adenosine accumulates under conditions of cellular stress including during made by scientists at the Beatson Institute and Institute of tumour development and this study provides a Cancer Sciences in the past year. mechanism that links this change in metabolism to the induction of cell death via the tumour suppressor p53. The authors use microarray Cheung EC, Athineos D, Lee P, Ridgway RA, Oncogene-induced senescence (OIS) blocks data to identify A2B, the adenosine receptor, as Lambie W, Nixon C, Strathdee D, Blyth K, cancer development by acting as a brake and a p53 target gene. They go on to show how A2B Sansom OJ, Vousden KH. stopping cell proliferation. However, little is is upregulated by p53 and then activates TIGAR is required for efficient intestinal known about the metabolism involved in this apoptosis upon adenosine binding. regeneration and tumorigenesis. Dev Cell process. This study uses metabolic profiling and 2013; 25: 463-77 functional perturbations to show that pyruvate Lourenco FC, Munro J, Brown J, Cordero J, dehydrogenase (PDH), an enzyme that ties Stefanatos R, Strathdee K, Orange C, Feller SM, In this study, the authors generate a TIGAR- glucose metabolism to oxidative Sansom OJ, Vidal M, Murray GI, Olson MF. deficient mouse and demonstrate the phosphorylation, is a crucial mediator of OIS in Reduced LIMK2 expression in colorectal cancer importance of this fructose-2,6-bisphosphatase melanoma induced by the oncogene reflects its role in limiting stem cell proliferation. in regulating glucose metabolism during BRAF(V600E). Furthermore, induction of PDH Gut 2014; 63: 480-93 intestinal regeneration and adenoma activity blocks melanoma growth and development. They conclude that TIGAR progression in vivo, leading the authors to In this work, the authors demonstrate that a contributes to both tissue regeneration and suggest that the relationship between OIS and reduction in LIM kinase 2 expression in tumour development and thus could be a PDH might be exploited therapeutically. colorectal cancer is associated with shorter potential therapeutic target in diseases such as patient survival. They also show, using ulcerative colitis and intestinal cancer. Klejnot M, Gabrielsen M, Cameron J, genetically modified Drosophila and mouse Mleczak A, Talapatra SK, Kozielski F, Pannifer models, that LIM kinase 2 can constrain Dou H, Buetow L, Sibbet GJ, Cameron K, A, Olson MF. gastrointestinal stem cell proliferation and thus Huang DT. Analysis of the human cofilin 1 structure reveals colon tumour development. Essentiality of a non-RING element in priming conformational changes required for actin donor ubiquitin for catalysis by a monomeric binding. Acta Crystallogr D Biol Crystallogr Ma Y, Li A, Faller WJ, Libertini S, Fiorito F, ROS production and NF-kappaB activation E3. Nat Struct Mol Biol 2013; 20: 982-6 2013; 69: 1780-8 Gillespie DA, Sansom OJ, Yamashiro S, triggered by RAC1 facilitate WNT-driven Machesky LM. intestinal stem cell proliferation and colorectal This paper describes the crystal structure of a In this paper, the authors determine the crystal Fascin 1 is transiently expressed in mouse cancer initiation. Cell Stem Cell 2013; 12: 761-73 monomeric RING E3 ligase. RING E3 ligases structure of a C147A point mutant of human melanoblasts during development and transfer ubiquitin from E2 to substrate during cofilin 1, a protein that disassembles actin promotes migration and proliferation. In this paper, the authors demonstrate that the ubiquitination, a process that regulates protein filaments and contributes to remodelling of the Development 2013; 140: 2203-11 GTPase RAC1 is a critical mediator of degradation and which is important for many actin cytoskeleton.
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