The Bmi1/BMP connection in medulloblastoma pathogenesis

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

Abstract

Medulloblastoma are the commonest brain cancers seen in young children. They have a poor survival rate despite improvements in some of the current treatment methods. We have recently shown that a gene called Bmi1 is strongly expressed in a significant proportion of these tumours. We now want to understand more in detail how this gene might control the growth of medulloblastoma. Especially we want to test the hypothesis that the expression of Bmi1 identifies a group of medulloblastoma which could be sensitive to treatment with molecules called BMPs.
There are studies in mouse models which show that BMPs inhibit growth of medulloblastoma. We want to assess whether this holds true also in cells derived from human tumours grown into recipient mice (xenograft).
We also aim to test if regulation of BMP by Bmi1 might affect the way cells interact with each other. This could enable us to understand how medulloblastoma spread and infiltrate the surrounding brain and distant organs.

Technical Summary

Medulloblastoma are the most common malignant brain tumours of childhood and they are still associated with high morbidity and mortality. The PcG gene Bmi1 is overexpressed in a significant proportion of human medulloblastoma and it induces and maintains tumour growth in several model systems. Our unpublished data in medulloblastoma cell lines show that repression of BMP signalling pathway through Bmi1 is a crucial pathogenetic event in medulloblastoma, which leads to deregulation of cell adhesion and of cell-extra cellular matrix interactions.

Aims and Objectives:
To elucidate the contribution to tumour growth of Bmi1 mediated repression of BMP pathway in a xenograft model of human medulloblastoma and in a genetically engineered mouse model. To provide proof of principle that Bmi1 expression identifies medulloblastoma, the growth of which can be counteracted by BMP treatment in a xenograft model.

Design and Methodology:
Human primary medulloblastoma cells :
Human primary medulloblastoma cells will be obtained from the Paediatric Brain Tumour Xenograft Consortium and will be screened for Bmi1 expression. Bmi1 will be downregulated with shRNA and BMP pathway upregulation will be validated. Furthermore, functional assays to study effects on cell adhesion properties in relation to Bmi1 expression profile will be performed. The candidate genes controlled by Bmi1 through BMP pathway repression will be identified and validated in tissue microarrays of human medulloblastoma.

Xenograft model:
Xenografts will be generated in NOD/SCID mice by intracerebellar injection of selected human primary medulloblastoma cell lines upon Bmi1 knock down and tumour growth will be monitored as compared to control xenografts. Xenografts will also be established from human primary medulloblastoma cell lines either overexpressing Bmi1 or with basal level of Bmi1 expression upon treatment with BMPs. Analysis of incidence, latency, biological behaviour and histological characteristics of the tumours will be performed.

Genetically engineered mouse model:
Bmi1 deficiency has been shown to impair medulloblastoma development in a mouse model - NeuroD2Smo*A1;Bmi1-/-. We will use this model to analyse the contribution of Bmi1 mediated repression of the BMP pathway and deregulation of cell adhesion to medulloblastoma growth.

Scientific and medical opportunities:
The current medulloblastoma treatment is based on non specific antiproliferative
therapies which do not take into account the specific, often unknown, mechanism driving tumour
growth in each tumour subgroup. The characterisation of the role of Bmi1/BMP in medulloblastoma pathogenesis will have implications for risk stratification of patients and for development of more targeted and less toxic therapeutic strategies for these neoplasms.

Publications

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Barritt A (2016) MASS ON SCAN OR MASSON SCAN in Journal of Neurology, Neurosurgery & Psychiatry

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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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Marchant R (2016) HICKAM'S DICTUM VERSUS OCKHAM'S RAZOR in Journal of Neurology, Neurosurgery & Psychiatry

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

 
Description Academic Clinical Lecturership
Amount £1 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 07/2014 
End 07/2018
 
Description BNS Small Grants Scheme
Amount £4,764 (GBP)
Organisation British Neuropathological Society 
Sector Learned Society
Country United Kingdom
Start 11/2013 
 
Description Barts Cancer Research Fund
Amount £8,000 (GBP)
Funding ID 527/2087 
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
 
Description Euro-CNS Travel Grant
Amount € 550 (EUR)
Organisation European Confederation of Neuropathological Societies 
Sector Learned Society
Country Italy
Start 10/2015 
End 11/2015
 
Description Pathological Society Small Grants Scheme
Amount £10,000 (GBP)
Funding ID SGS2013/04/03 
Organisation Pathological Society of Great Britain & Ireland 
Sector Learned Society
Country United Kingdom
Start 01/2014 
 
Description Travel and Conference Bursary
Amount £218 (GBP)
Funding ID T&CB 2011 05 
Organisation Pathological Society of Great Britain & Ireland 
Sector Learned Society
Country United Kingdom
Start 12/2011 
End 02/2012
 
Description Bioinformatics for transcriptomic analysis 
Organisation Queen Mary University of London
Department Barts and The London School of Medicine and Dentistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Project design and establishment of the experimental methods to carry out the project
Collaborator Contribution Provides bioinformatics support for the transcriptomic analysis included in our project.
Impact No output so far, data generation stage
Start Year 2011
 
Description Correlation mouse/human medulloblastoma findings 
Organisation Hospital for Sick Children, Toronto
Department Department of Neurosurgery
Country Canada 
Sector Hospitals 
PI Contribution Develop original research data on mouse models
Collaborator Contribution Analysis of correlations with human datsets
Impact No output yet.
Start Year 2012
 
Description Preclinical model of medulloblastoma 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Department Centre for Neuropathology and Prion Research (ZNP)
Country Germany 
Sector Academic/University 
PI Contribution Develop original research question on primary cell culture of human medulloblastoma and on a xenograft model to be validated on a genetically engineered mouse model
Collaborator Contribution Provide genetically engineered mouse model for validation of our findings on human primary medulloblastoma cells and xenografts
Impact The project is in progress.
Start Year 2012
 
Description Primary Human Medulloblastoma Cells 
Organisation Baylor College of Medicine
Department Department of Pediatrics
Country United States 
Sector Academic/University 
PI Contribution We have contributed the hypothesis to be tested and we have designed the experimental plan. We have established experimental methods to carry forward the project.
Collaborator Contribution Our collaborators have provided us primary human cancer cells which are crucial for our project.
Impact As an early outcome, our collaborator have provided us with primary human medulloblastoma cells which are crucial for the progress of our project.
Start Year 2011
 
Description Temozolomide resistant glioblastoma project 
Organisation Queen Mary University of London
Department Centre for Molecular Oncology
Country United Kingdom 
Sector Hospitals 
PI Contribution We have contributed in generation of intracranial xenografts for in vivo mouse model. My supervisor and I would be examining the tissue specimens and providing professional opinion on histopathology diagnosis.
Collaborator Contribution Our partners are conceiving this project and performing majority of the experiments and data collection.
Impact There are no outputs from this collaboration yet, but we are expecting to prepare and submit the manuscript by early 2014.
Start Year 2013
 
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 ATP training 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Health professionals
Results and Impact 10-15 trainee mortuary techniticians attended the training session.

The students were very pleased with the new knowledge.
Year(s) Of Engagement Activity 2010,2011
 
Description Article on Academic Training 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact In Summer 2012, article titled 'Pipettes, PCR, Proteins and More. Academic Training: Is This for You?' was published in Association of Clinical Pathologists (ACP) news bulletin, trainees' zone. I have also attempted to encourage the readers to develop an interest in academic/research training.

A positive feedback from the editor the ACP news bulletin regarding this article.
Year(s) Of Engagement Activity 2012
 
Description BNS Academic Discussion Forum 
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 I was involved in organising an 'academic discussion' workshop session for national neuropathology trainees. This is to encourage neuropathology trainees (junior doctors training in neuropathology specialty), to be trainees and post graduate students to involve in research and academic activities. This session was also designed to support those who are already involved in research and those who are planning to set up new research projects. This first session was chaired by Dr Tom Jacques and Prof Silvia Marino.
The session saw active participation from all attendees and there was an increased interest in academia generated.
Year(s) Of Engagement Activity 2017
URL http://www.bns.org.uk/
 
Description British Neuro-Oncology Society 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Health professionals
Results and Impact I presented my research data as an oral poster presentation at British Neuro-Oncological Society (BNOS) Conference, held in Cambridge, 29 June - 01 July 2011.
My presentation was awarded best oral poster presentation. I was asked to write a brief article for the BNOS Newsletter which was published in August 2011 (Number 05/11).

This has helped for members of BNOS to learn about research activities in neuroscience. It has also helped me to learn about BNOS and to consider applying for BNOS membership.
Year(s) Of Engagement Activity 2011
 
Description Centre of the Cell 2016 
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 I was involved with facilitation of centre of the cell activity at the Blizard Institute of Queen Mary University of London, where school pupils are educated about biological sciences and institute's research is showcased. The activity brought about enthusiasm in medical/biological science and research among the attendees.
Year(s) Of Engagement Activity 2016
 
Description Facilitation of Centre of the Cell Activity 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact I was involved in three separate workshops in 2013, involving about 60 students altogether. Several students were motivated in science and asked keen questions after the show.

There is an increasing interest for schools to visit Centre of the Cell.
Year(s) Of Engagement Activity 2013
URL http://www.centreofthecell.org/index.php
 
Description Launch of Brain Tumour Research Excellence Centre 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact About 60 people attended the launch event among whom were brain tumour patients, carers and family, charity trustees, politicians and media personnel. There was a very good response to the tour of the lab and presentations given and generated active discussion during and after the event.

There was an increase in interest for fundraising and support from the public and politician.
Year(s) Of Engagement Activity 2014
URL http://my.qmul.ac.uk/news_and_events/2014/141951.html
 
Description NIHR Trainees Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Title of the workshop: Integrated Academic Training, 27 September 2018, London. I presented my research and spoke about my career progression with aid of NIHR funded Clinical Lecturership. The audience were mainly NIHR academic clinical fellows and clinical lecturers and specialty trainees across QMUL. There was good interest from the attendees and many aspiring academic trainees showed motivation to continue or persue academics
Year(s) Of Engagement Activity 2018
 
Description National Pathology Week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact More than 20 school students attended the event. They were very keen to be educated further.

The event was successful and well recieved. Further similar events requested.
Year(s) Of Engagement Activity 2009
 
Description National Pathology Year 2012 
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 Regional
Primary Audience Public/other audiences
Results and Impact I will be participating in the National Pathology Year 2012 event 'Promoting Pathology' (Organiser - Sarah Pitkin) to be held on 29th November 2012 at The Royal London Hospital. I look forward to this event which is aimed at generating pathology awareness to the general public and hospital staff.

To be held on 29th November 2012
Year(s) Of Engagement Activity 2012
 
Description Pathology Trainees Academic Forum 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Title of the workshop: School of Pathology Academic Forum, 2018, London. I presented my research and spoke about my career progression with aid of MRC CRTF and NIHR funded Clinical Lecturership. The audience were mainly academic clinical fellows and clinical lecturers and Pathology specialty trainees across London Deanery. There was good interest from the attendees and many aspiring academic trainees showed motivation to continue or persue academics
Year(s) Of Engagement Activity 2018
 
Description Presentation at Barts charity symposium 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact I was one of the presenters in Barts charity symposium held on 30.11.2017, representing our research group and presenting update on research progress made. The audience comprised of charity supporters, charity members and trustees. It was an opportunity to showcase our outputs with potential to gain further grant awards.
Year(s) Of Engagement Activity 2017
 
Description RCPath workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact This workshop is centred around discussion exploring the views of young people on different aspects of the new Human Tissue Act 2004. There was a keen participation by the audience. They felt they were educated and informed by this workshop.
Year(s) Of Engagement Activity 2015,2016
URL https://www.rcpath.org/event/your-body-your-consent.html
 
Description STEM Ambassador 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact At Barts and the London School of Medicine and Dentistry, we have an established educational charity - 'Centre of the Cell' aimed for school students and general public. There is a state of the art 'Pod' which offers fun filled interactive way of learning science to the visitors. As a STEM ambassador, I have been involved in demonstration of the Pod sessions. I mainly demonstrate histopathology slides and gross specimens, explaining the pathology of diseases and answer any questions


At then end of the sessions the students express their gratitude for having learnt more about science. They are more aware of the career opportunities as scientists and researchers.
Year(s) Of Engagement Activity 2012
URL http://www.stemnet.org.uk