Somatic gene delivery faithfully recapitulates a molecular spectrum of high-risk sarcomas
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.
Authors
- Lukas Theo Schmitt (ORCID: https://orcid.org/0000-0002-5455-4901)
- Patrick Günther (ORCID: https://orcid.org/0000-0002-9135-7819)
- Ina Oehme (ORCID: https://orcid.org/0000-0002-0827-2356)
- Florencia Cidre‐Aranaz (ORCID: https://orcid.org/0000-0002-0246-7179)
- Felix K. F. Kommoss (ORCID: https://orcid.org/0000-0003-0876-9087)
- Thomas G. P. Grünewald (ORCID: https://orcid.org/0000-0003-0920-7377)
- Roland Imle (ORCID: https://orcid.org/0000-0001-9564-6952)
- Christina Blume (ORCID: https://orcid.org/0000-0003-1438-9304)
- Heike Peterziel (ORCID: https://orcid.org/0000-0001-9261-7144)
- Florian H. Geyer
- Robert J. Autry (ORCID: https://orcid.org/0000-0002-6965-2942)
- Christian Seitz (ORCID: https://orcid.org/0000-0002-0520-7866)
- Sophia Scheuermann (ORCID: https://orcid.org/0000-0003-0487-2773)
- Stefan M. Pfister (ORCID: https://orcid.org/0000-0002-5447-5322)
- Claudia Winter
- Claudia Scholl (ORCID: https://orcid.org/0000-0001-6768-322X)
- Kevin B. Jones (ORCID: https://orcid.org/0000-0003-1531-2157)
- Eric Stutheit-Zhao
- Ana Banito (ORCID: https://orcid.org/0000-0003-2188-0003)
- Priya Chudasama (ORCID: https://orcid.org/0000-0002-0754-4436)
- Michael Hertwig (ORCID: https://orcid.org/0000-0003-0534-098X)
- Lena Wagner
- Martin Sill (ORCID: https://orcid.org/0000-0001-7616-7665)
- Christian Vokuhl (ORCID: https://orcid.org/0000-0002-4138-4536)
- Sara Placke
- Malte von Eicke
- Dmitry Lupar
- Daniel Blösel
- Claudia Schmidt (ORCID: https://orcid.org/0000-0001-8532-2604)
- Stephanie Laier
- Hannah Walzer
- Р.В. Редькин
Institutions
- University of Bonn (DE)
- German Cancer Research Center (DE)
- University of Utah (US)
- Heidelberg University (DE)
- Huntsman Cancer Institute (US)
- University Hospital Heidelberg (DE)
- National Center for Tumor Diseases (DE)
- Hopp Children's Cancer Center Heidelberg (DE)
- DKFZ-ZMBH Alliance (DE)
- University of Tübingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-16
- DOI
- https://doi.org/10.1038/s41467-025-60519-5
- Citations
- 4
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 4.18
Funders
- Deutsches Krebsforschungszentrum
- European Commission
- Deutsche Forschungsgemeinschaft
- Universität Heidelberg
- Bundesministerium für Bildung und Forschung