2. Academic Validation
  3. Somatic gene delivery faithfully recapitulates a molecular spectrum of high-risk sarcomas

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

  • Nat Commun. 2025 Jun 16;16(1):5283. doi: 10.1038/s41467-025-60519-5.
Roland Imle 1 2 3 4 5 6,  Daniel Blösel 1 2 3 6,  Felix K F Kommoss 1 2 3 7,  Sara Placke 1 2 3 6,  Eric Stutheit-Zhao 2 3 8 9,  Christina Blume 9 10 11,  Dmitry Lupar 1 2 3,  Lukas Schmitt 1 2 3,  Claudia Winter 1 2 3,  Lena Wagner 1 2 3,  Malte von Eicke 1 2 3,  Hannah Walzer 12,  Julia Förderer 12,  Stephanie Laier 12,  Michael Hertwig 13,  Heike Peterziel 2 3 9 14,  Ina Oehme 2 3 9 14,  Sophia Scheuerman 2 3 4 14 15,  Christian M Seitz 2 3 4 14,  Florian H Geyer 2 3 9 16 17,  Florencia Cidre-Aranaz 2 3 9 16,  Thomas G P Grünewald 2 3 7 9 16,  Christian Vokuhl 18,  Priya Chudasama 9 19,  Claudia Scholl 3 9 20,  Claudia Schmidt 21,  Patrick Günther 5,  Martin Sill 2 3 8 9,  Kevin B Jones 22 23,  Stefan M Pfister 2 3 8 9,  Robert J Autry 24 25 26 27,  Ana Banito 28 29 30
Affiliations

Affiliations

  • 1 Soft-tissue sarcoma research group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 2 Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • 3 National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
  • 4 Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
  • 5 Division of Pediatric Surgery, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
  • 6 Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany.
  • 7 Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
  • 8 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 9 German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany.
  • 10 Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
  • 11 Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 12 Core Facility Tumor Models, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 13 Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
  • 14 Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 15 Department of Pediatric Hematology and Oncology, University Hospital Tuebingen, Tuebingen, Germany.
  • 16 Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 17 Faculty of Medicine, Heidelberg University, Heidelberg, Germany.
  • 18 Section of Pediatric Pathology, Department of Pathology, University of Bonn, Bonn, Germany.
  • 19 Precision Sarcoma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 20 Division of Applied Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 21 Core Facility Light Microscopy, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 22 Department of Orthopaedics, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • 23 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • 24 Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. robert.autry@kitz-heidelberg.de.
  • 25 National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany. robert.autry@kitz-heidelberg.de.
  • 26 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. robert.autry@kitz-heidelberg.de.
  • 27 German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. robert.autry@kitz-heidelberg.de.
  • 28 Soft-tissue sarcoma research group, German Cancer Research Center (DKFZ), Heidelberg, Germany. a.banito@kitz-heidelberg.de.
  • 29 Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. a.banito@kitz-heidelberg.de.
  • 30 National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany. a.banito@kitz-heidelberg.de.
PMID: 40523919 DOI: 10.1038/s41467-025-60519-5
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.

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