Epigenetic control of stem cell identity in rhabdoid sarcomas
Sarcomas characterized by the deficiency of SWI/SNF chromatin remodeling, including rhabdoid and synovial sarcomas, remain mostly lethal in spite of intensive chemotherapy, surgery and radiotherapy. Normal cells do not tolerate mutations of genes encoding SWI/SNF complexes, suggesting the existence of cooperating mechanisms that allow sarcoma cells to tolerate their deficiency and promote tumorigenesis. Rhabdoid sarcomas are known to be driven by abnormal regulation of gene expression, but its mechanisms remain elusive. Our recent work revealed an unanticipated requirement of an endogenous DNA transposase for the development of rhabdoid sarcomas. Its enforced expression is sufficient to induce malignant transformation of normal human cells with stem cell-like gene expression programs, and its activity is required for the survival of sarcoma cells driven by aberrant chromatin remodeling. The current project aims to determine the mechanisms of aberrant cell survival in rhabdoid sarcomas and its control by the sarcoma DNA transposase using chromatin mapping technologies in vitro and faithful genetically-engineered mouse sarcoma models in vivo. This knowledge will be used to identify specific molecular dependencies that may be used for the development of improved targeted therapies of refractory sarcomas.