Somatic gene delivery faithfully recapitulates a molecular spectrum of high-risk sarcomas
- Roland Imle
- Daniel Blösel
- Felix K. F. Kommoss
- Sara Placke
- Eric Stutheit-Zhao
- Christina Blume
- Dmitry Lupar
- Lukas Schmitt
- Claudia Winter
- Lena Wagner
- Malte von Eicke
- Hannah Walzer
- Julia Förderer
- Stephanie Laier
- Michael Hertwig
- Heike Peterziel
- Ina Oehme
- Sophia Scheuerman
- Christian M. Seitz
- Florian H. Geyer
- Florencia Cidre-Aranaz
- Thomas G. P. Grünewald
- Christian Vokuhl
- Priya Chudasama
- Claudia Scholl
- Claudia Schmidt
- Patrick Günther
- Martin Sill
- Kevin B. Jones
- Stefan M. Pfister
- Robert J. Autry
- Ana Banito
2025-06-16
A major challenge hampering therapeutic advancements for high-risk sarcoma patients is the broad spectrum of molecularly distinct sarcoma types and the corresponding lack of suitable model systems. Here we describe the development of a genetically-controlled, yet versatile mouse modeling platform allowing delivery of different genetic lesions by muscle electroporation (EPO) in wildtype mice. This EPO-GEMM (EPO-based genetically engineered mouse model) platform allows the generation of ten genetically distinct sarcomas on an isogenic background, including the first model of ETV6::NTRK3 -driven sarcoma. Comprehensive histological and molecular profiling reveals that this mouse sarcoma cohort recapitulates a spectrum of molecularly diverse sarcomas with gene fusions acting as major determinants of sarcoma biology. Integrative cross-species analyses show faithful recapitulation of human sarcoma subtypes, including expression of relevant immunotherapy targets. Comparison of syngeneic allografting methods enables reliable preservation and scalability of sarcoma-EPO-GEMMs for preclinical treatment trials, such as NTRK inhibitor therapy in an immunocompetent background.