Molecular dissection of c-Myc function in self renewal/differentiation of neural stem cells

Lead Research Organisation: Queen Mary, University of London
Department Name: Blizard Institute of Cell and Molecular

Abstract

Recent discoveries in cell biology have shown that genes previously implicated in a variety of forms of cancer are also key regulators of the proliferation of normal stem cells. Various signals instruct cells whether to grow or to stop and become a particular cell type. These signals are crucial for proper organ function because the formation of a specific organ depends on the right amount of cell growth being balanced with the right ratio of cells forming differentiated and specialised cells.

Here we will focus on brain stem cells and we will perform experiments to examine the function of particular genes, c-Myc and Bmi1, in regulating basic stem cell properties, such as proliferation/self renewal and differentiation. We hope these studies will provide insight into how neural stem cells are regulated during brain development and in neurogenic area of the adult brain.

Understanding how specific genes promote the proliferation of neural stem cells will allow us to set the basis for a potential future development of new treatments for currently incurable brain diseases and injuries.

Technical Summary

In this proposal, we want to test the hypothesis that the molecular mechanisms that were originally identified to govern c-Myc function in tumourigenesis, also regulate its physiological function in stem cells.

We will use a combined in vitro and in vivo neural stem cell model to address this question. We will take advantage of a unique set of genetically modified mice, which are either already available in our laboratories or which will be generated in the context of this grant application. In particular we plan to generate compound mutant mice overexpressing c-Myc and the Polycomb group gene Bmi1, to assess whether these two genes act synergistically in controlling self renewal and differentiation of subventricular zone neural stem cell. Moreover a combination of genome-wide gene expression analysis and a systematic approach to identify the set of promoters bound by c-Myc and Bmi-1 will be performed on normal and transgenic SVZ stem cells to identify unknown effectors of neural stem cell biological functions.

Understanding the molecular mechanisms regulating the biological properties of neural stem cells is crucial for a potential future development of new therapeutic strategies for brain diseases and injuries, which are currently characterised by a dismal prognosis.

Publications

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Guillotin D (2017) Drug-Repositioning Screens Identify Triamterene as a Selective Drug for the Treatment of DNA Mismatch Repair Deficient Cells. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Leto K (2016) Consensus Paper: Cerebellar Development. in Cerebellum (London, England)

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Merve A (2014) OP10 * ROLE OF C-MYC IN CHOROID PLEXUS TUMOURS in Neuro-Oncology

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Merve A. (2016) c-Myc in choroid plexus tumourigenesis in NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY

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Merve Ashirwad (2014) ROLE OF C-MYC IN CHOROID PLEXUS TUMOURS in NEURO-ONCOLOGY

 
Description APPG Brain Tumours
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description All-Party Brain Tumour Group
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description British Neuro-Oncology Society Council Member
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description British Neuropathology Society Academic Committee Chair
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Cabinet Office Roundtable on a global strategy to support brain tumour research in the UK and abroad
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description Chair Scientific Advisory Board Children with Cancer UK
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact I am the chair of a SAB which allocates funding to young medical postgraduate trainees to gain and refine skills in all aspects of childhood cancer.
 
Description Council Member NCRI Clinical Study Group Brain
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Lead NIHR Integrated Academic Clinical Training at QMUL
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description MRC/Brain Tumour Research Workshop
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Member of Scientific Advisory Board - Children with Cancer UK
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Impact as above achieved by providing appropriate funding for research project to advance treatment and for clinical initiative for patients benefit.
 
Description Member of the scientific committee European Association for Neuro-Oncology
Geographic Reach Asia 
Policy Influence Type Membership of a guidance committee
 
Description Vice-President of the British Neuro-oncology Society
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description 1year Clinical Research Training Fellowship for a neurosurgery trainee
Amount £57,641 (GBP)
Organisation Royal College of Surgeons of England 
Sector Learned Society
Country United Kingdom
Start 08/2010 
End 07/2011
 
Description 2year Clinical Research Training Fellowship for a neurosurgery trainee
Amount £195,000 (GBP)
Organisation Sparks 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2011 
End 07/2013
 
Description Barts Charity - Programme Grant
Amount £1,500,000 (GBP)
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2019 
End 12/2024
 
Description Brain Tumour Research Centre of Excellence
Amount £3,300,000 (GBP)
Organisation Brain Tumour Research 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 12/2019
 
Description Clinical Research Training Fellowship for a neuropathology trainee
Amount £43,789 (GBP)
Organisation Mason Medical Research Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 10/2016
 
Description Intramural matched funding for BTR CoE award
Amount £204,000 (GBP)
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2015 
End 02/2018
 
Description MRC CRTF for a neuropathology trainee
Amount £266,500 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2010 
End 10/2013
 
Description MRC Project grant scheme
Amount £635,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 12/2015 
End 11/2018
 
Description MRC/BTC Clinical Research Training Fellowship to a neuropathology trainee (Marino Supervisor)
Amount £246,281 (GBP)
Organisation The Brain Tumour Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description PhD Studentship
Amount £98,000 (GBP)
Organisation Ataxia UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description PhD studentship
Amount £85,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 09/2016
 
Description Postdoctoral Fellowship
Amount £373,000 (GBP)
Organisation Children with Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2014 
End 08/2019
 
Description Project grant
Amount £192,000 (GBP)
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2012 
End 02/2015
 
Description Pump Priming Fund
Amount £27,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 12/2012 
End 05/2013
 
Description Small Grant Scheme for a neuropathology trainee
Amount £10,000 (GBP)
Organisation Pathological Society of Great Britain & Ireland 
Sector Learned Society
Country United Kingdom
Start 01/2016 
End 12/2016
 
Title Trascriptomic datasets 
Description Whole genome trascriptomic datasets deposited in openly accessible repositories 
Type Of Material Biological samples 
Year Produced 2013 
Provided To Others? Yes  
Impact Facilitate meta-analysis of research data 
 
Title c-Myc conditional overexpressing mouse line 
Description New mouse line allowing to overexpress c-Myc in a conditional fashion 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact This is a unique tool, which will allow to model and understand the function of c-Myc in normal cells and cancer. 
 
Description CRUK Multicentre Accelerator Award 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution I have contributed to the writing of the application as a named collaborator, I will contribute my clinical neuropathological knowledge and my scientific expertise in brain tumour biology to the consortium.
Collaborator Contribution I will gain access to tumour samples and cell lines generated and characterised through the consortium, my research team and I will attend research meetings and profit from the overall expertise and resources of the consortium. We will link to the bioinformatics hub to be established by the consortium.
Impact No output yet, collaboration just started.
Start Year 2016
 
Description Cancer evolution in syngeneic tumour/iNSC pairs 
Organisation Queen Mary University of London
Department Barts Cancer Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Generation and characterisation of primary lines, generation of epigenomic datasets, contribution to design of experiments
Collaborator Contribution Knowledge on cancer evolution, computational modelling, contribution to design of experiments.
Impact Currently working on a grant proposal to be submitted to CRUK
Start Year 2018
 
Description Computational modelling and analysis of epigenetic datasets 
Organisation Uppsala University
Country Sweden 
Sector Academic/University 
PI Contribution Generation of unique epigenomic datasets for collaborative research, formulate research questions
Collaborator Contribution Bioinformatic analytical skills and computational modelling
Impact Multidisciplinary: bioinformatics, mathematical modelling, epigenomics, cellular and molecular biology
Start Year 2017
 
Description Correlation of epigenetic datasets with proteomic datasets 
Organisation Curie Institute Paris (Institut Curie)
Country France 
Sector Academic/University 
PI Contribution Original hypothesis to be tested, new epigenomics datasets.
Collaborator Contribution Published and unpublished proteomics datasets, computational correlation pipeline.
Impact Collaboration just started
Start Year 2019
 
Description Drug screening for high grade glioma 
Organisation Queen Mary University of London
Department Barts Cancer Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Charaterisation of human primary glioma cells Analysis of xenografts Pathological expertise
Collaborator Contribution Hypothesis to be tested Screening tools
Impact £192k funding from Barts and The Lodnon Charity
Start Year 2011
 
Description Epigenome of NSC 
Organisation Medical Research Council (MRC)
Department MRC Cell Biology Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Hypothesis to be tested Unique reagents Design of experimental plan
Collaborator Contribution Access to facilities, Sharing unpublished data Bioinformatics expertise
Impact Ongoing, no outputs yet
Start Year 2011
 
Description Epigenome of NSC 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Hypothesis to be tested Unique reagents Design of experimental plan
Collaborator Contribution Access to facilities, Sharing unpublished data Bioinformatics expertise
Impact Ongoing, no outputs yet
Start Year 2011
 
Description Epigenome of neural stem cells and glioblastoma 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Hypothesis to be tested Essential reagents and knowledge Leadership of the project
Collaborator Contribution Access to tissue and primary cells Essential knowledge
Impact Centre of excellence award by the charity Brain Tumour Research, £3,300,000 over 5 years.
Start Year 2013
 
Description High throughput drug screening 
Organisation Sanford-Burnham Medical Research Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Generated edited primary lines and controls for screening, formulated scientific questions and contributed to experimental screening plan
Collaborator Contribution High throughput compound screening expertise, designed experimental plan for deconvolution
Impact Collaboration just started, no output so far
Start Year 2017
 
Description Nanoparticles as drug delivery tool to stem cells 
Organisation Queen Mary University of London
Department School of Biological and Chemical Science QMUL
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in neural stem cell biology Hypothesis to be tested Design of experiments
Collaborator Contribution Expertise in nanoparticles Hypothesis to be tested Design of experiments
Impact £27k award over 6 months from EPSRC/QM
Start Year 2012
 
Description Nanoparticles as drug delivery tool to stem cells 
Organisation University of Warwick
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in neural stem cell biology Hypothesis to be tested Design of experiments
Collaborator Contribution Expertise in nanoparticles Hypothesis to be tested Design of experiments
Impact £27k award over 6 months from EPSRC/QM
Start Year 2012
 
Description Regulation of survivin by Bmi1 
Organisation Italian Foundation for Cancer Research
Department FIRC Institute of Molecular Oncology Foundation
Country Italy 
Sector Public 
PI Contribution Hypothesis to be tested Unique reagents Design of experimental plan
Collaborator Contribution Sharing of reagents (constructs and mouse models).
Impact Joint grant application Publication: PMID: 23132836
Start Year 2010
 
Description c-Myc dataset 
Organisation European Institute of Oncology (IEO)
Country Italy 
Sector Charity/Non Profit 
PI Contribution We identified a gene signature in human choroid plexus tumours expressing high levels of cMyc
Collaborator Contribution They have helped in comparison of our gene signature with their ChIPSeq/RNASeq data.
Impact The project is still on going and there are no outputs yet, but the results are expected to be submitted for publication in 2016.
Start Year 2016
 
Description Article for The Conversation (online) and printed in i Newspaper 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Written an article on clinical trials in near-oncology.
Year(s) Of Engagement Activity 2018
 
Description Centre of The Cell - Contribution 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact My group,including staff funded by his grant, regularly contributes mateirla, such as slides, cartoons etc. to Centre of the Cell. Centre of the Cell is custom-made, interactive environment in which scientists can efficiently discuss and debate their research with young people.

This is a combination of digital technologies and real-world science that creates a science education experience not available in the classroom.
Year(s) Of Engagement Activity 2009
 
Description Laboratory Tour for the public 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Series of 6 Lab Tours per year: Guided laboratory visits, discussions of current research topics, demonstrations of research activities. Mentoring of junior lab members while taking part in public engagement activities.
Year(s) Of Engagement Activity 2015,2016,2017,2018
 
Description Lay presentation at Ataxia UK Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact >50 people attended the event

lively discussion after my talk with many questions
Year(s) Of Engagement Activity 2012
 
Description MRC/Brain Tumour Research Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The aim of the workshop was to identify crossdisciplinary research opportunities between neuroscience and brain tumour research. I have contributed to organising the workshop, moderated one session and given a talk.
Year(s) Of Engagement Activity 2018
 
Description Media Coverage of the Launch of the BTR Centre of excellence 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact TV and radio interviews

Received many emails form patients, carers and general public
Year(s) Of Engagement Activity 2014
 
Description Meeting with fundraiser, patients and interested member of the public 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact I estimate approximately 80 people attended the meeting, the discussion was lively, several questions were asked after the talk and at the reception after the talk.

Further similar activities are planned
Year(s) Of Engagement Activity 2010
 
Description National Pathology Year Event 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Stalls representing Clinical Biochemistry, Haematology, Immunology, Virology and Histopathology gave staff, patients and the general public an opportunity to speak to professionals in each discipline and even to try their hand at some Pathology tests.


Increase interest of the the general public in Pathology
Year(s) Of Engagement Activity 2011,2012
 
Description SPARKS Site visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Lay representatives of the charity visited our lab and were shown results of our research

The charity was very impressed with our achievements
Year(s) Of Engagement Activity 2012
 
Description Tessa Jowell Brain Cencer Mission 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact To design the national brain tumour research and training strategy.
Year(s) Of Engagement Activity 2018
URL http://www.thebraintumourcharity.org/get-involved/campaigning-for-change/what-were-campaigning/tessa...
 
Description Various activities to raise awareness of brain tumour research 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 4 Lab tours with ~20 attendees, attendance to parliamentary events organised by charities, attendance to fundraising events
Year(s) Of Engagement Activity 2015