Somatic muscle engineering faithfully recapitulates a molecular spectrum of high-risk sarcomas [RNA-Seq]

A particular challenge hampering therapeutic advancements for high-risk sarcoma patients is the broad spectrum of molecularly distinct sarcoma entities and the corresponding lack of suitable model systems to recapitulate and study these diseases. To overcome this predicament, we developed a novel genetically-controlled, yet versatile mouse modeling platform allowing delivery of different genetic lesions by electroporation (EPO) of the thigh muscle in wildtype mice. This sarcoma EPO-GEMM (EPO-based genetically engineered mouse model) platform allowed the generation of ten biologically distinct sarcoma entities and subtypes on an isogenic background, including the first model of ETV6::NTRK3-driven infantile fibrosarcoma and of BCOR-inactivated rhabdomyosarcoma. Comprehensive histological and molecular profiling revealed that this mouse sarcoma cohort recapitulates the molecular diversity observed across the human disease with gene fusion and Trp53 status acting as major determinants of sarcoma biology. Integrative cross-species analyses confirmed faithful recapitulation of the human disease, including the expression of relevant immunotherapy targets.