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.
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.
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.
Organisations
- Queen Mary, University of London, United Kingdom (Collaboration, Lead Research Organisation)
- University College London, United Kingdom (Collaboration)
- Italian Foundation for Cancer Research (Collaboration)
- Curie Institute Paris (Institut Curie) (Collaboration)
- Uppsala University (Collaboration)
- University of Warwick, United Kingdom (Collaboration)
- Sanford Burnham Medical Research Inst (Collaboration)
- Medical Research Council (Collaboration)
- European Institute of Oncology (Collaboration)
People |
ORCID iD |
| Silvia Marino (Principal Investigator) | |
| Axel Behrens (Co-Investigator) |
Publications
Acquati S
(2013)
Epigenetic regulation of survivin by Bmi1 is cell type specific during corticogenesis and in gliomas.
in Stem cells (Dayton, Ohio)
Blake SM
(2016)
Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation.
in eLife
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
Hoeck JD
(2010)
Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun.
in Nature neuroscience
Leto K
(2016)
Consensus Paper: Cerebellar Development.
in Cerebellum (London, England)
Merve A
(2014)
OP10 * ROLE OF C-MYC IN CHOROID PLEXUS TUMOURS
in Neuro-Oncology
Merve A
(2019)
c-MYC overexpression induces choroid plexus papillomas through a T-cell mediated inflammatory mechanism.
in Acta neuropathologica communications
Merve A.
(2016)
c-Myc in choroid plexus tumourigenesis
in NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
Merve Ashirwad
(2014)
ROLE OF C-MYC IN CHOROID PLEXUS TUMOURS
in NEURO-ONCOLOGY
Papadimitriou SA
(2016)
Fluorescent polymeric nanovehicles for neural stem cell modulation.
in Nanoscale
| 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 |