Somatic gene delivery faithfully recapitulates a molecular spectrum of high-risk sarcomas

Somatic gene delivery faithfully recapitulates a molecular spectrum of high-risk sarcomas

Abstract 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 pl...

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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2025-06-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-60519-5
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Summary:Abstract 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.
ISSN:2041-1723

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