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<p>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 <i>ETV6::NTRK3</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月16日

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  • 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

摘要

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.