Somatic gene delivery faithfully recapitulates a molecular spectrum of high-risk sarcomas
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.
Article Details
Authors (32)
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
Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany
Patrick Günther
Martin Sill
Kevin B. Jones
Stefan M. Pfister
Robert J. Autry
Ana Banito