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 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 () and Ana Banito ()
Additional contact information
Roland Imle: German Cancer Research Center (DKFZ)
Daniel Blösel: German Cancer Research Center (DKFZ)
Felix K. F. Kommoss: German Cancer Research Center (DKFZ)
Sara Placke: German Cancer Research Center (DKFZ)
Eric Stutheit-Zhao: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Christina Blume: core center Heidelberg
Dmitry Lupar: German Cancer Research Center (DKFZ)
Lukas Schmitt: German Cancer Research Center (DKFZ)
Claudia Winter: German Cancer Research Center (DKFZ)
Lena Wagner: German Cancer Research Center (DKFZ)
Malte Eicke: German Cancer Research Center (DKFZ)
Hannah Walzer: German Cancer Research Center (DKFZ)
Julia Förderer: German Cancer Research Center (DKFZ)
Stephanie Laier: German Cancer Research Center (DKFZ)
Michael Hertwig: German Cancer Research Center (DKFZ-ZMBH Alliance)
Heike Peterziel: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Ina Oehme: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Sophia Scheuerman: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Christian M. Seitz: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Florian H. Geyer: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Florencia Cidre-Aranaz: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Thomas G. P. Grünewald: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Christian Vokuhl: University of Bonn
Priya Chudasama: core center Heidelberg
Claudia Scholl: a partnership between DKFZ and Heidelberg University Hospital
Claudia Schmidt: German Cancer Research Center (DKFZ)
Patrick Günther: University Hospital Heidelberg
Martin Sill: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Kevin B. Jones: University of Utah School of Medicine
Stefan M. Pfister: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Robert J. Autry: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Ana Banito: German Cancer Research Center (DKFZ)

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60519-5

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