Objective
Malignant rhabdoid tumour (MRT) are highly aggressive malignant neoplasms of childhood. MRTs show great phenotypic variability in their tissue localisation and differentiation. This phenotypic diversity contrasts with a strong genetic homogeneity characterised by biallelic inactivation of hSNF5/INI1; a subunit of the SWI/SNF chromatin remodelling complex.
This phenotypic variability means that it is unclear in which type of cells MRTs arise. The aim of this proposal is to elucidate how hSNF5/INI1 affects the differentiation of MRTs with a view to identifying an MRT progenitor cell and to examine the role and molecular mechanism of hSNF5/INI1 in various key differentiation programmes.
Microarray expression analyses will be conducted comparing the transcription profiles of MRT lacking hSNF5/INI1 and of MRT cells manipulated to re-express hSNF5/INI1 with these of a variety of normal tissues and immature progenitor cells. In vitro differentiation experiments with MRT cell lines expressing a conditional version of h SNF5/INI1 will enable us to investigate the differentiation potentials of MRT cells from various origins (brain, epithelial, soft tissue).
Furthermore, the requirement for hSNF5/INI1 in well-documented models of cell differentiation (PC12, 3T3L1, C2C12, mesenchymal stem cells) will be evaluated by specifically silencing hSNF5/INI1.
These experiments will be combined with CHip on chip experiments (Chromatin Immunoprecipitation followed by microarray profiling) investigating the promoters bound by hSNF5/INI1 and temporal analysis of the gene expression profile of MRT cells following hSNF5/INI1 activation, this project should contribute to a better understanding of the cellular pathways controlled by hSNF5/INI1 and altered in MRT.
Overall, the project should contribute to a better understanding of both MRT tumourigenesis and the role of chromatin remodelling in cell differentiation.
Fields of science
Call for proposal
FP6-2005-MOBILITY-5
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Funding Scheme
EIF - Marie Curie actions-Intra-European FellowshipsCoordinator
PARIS
France