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.
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 Our unpublished data in medulloblastoma cell lines show that repression of BMP signalling pathway through Bmi1 is a crucial pathogenetic event in medulloblastoma, which leads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.
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.