Somatic gene delivery faithfully recapitulates a molecular spectrum of high-risk sarcomas PMID: 40523919

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
25. National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany. [email protected].
26. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
27. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. [email protected].
28. Soft-tissue sarcoma research group, German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
29. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. [email protected].
30. National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany. [email protected].

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.