Rahil Noorizadeh Rahil Noorizadeh Barbara Sax Barbara Sax Tahereh Javaheri Tahereh Javaheri Branka Radic-Sarikas Branka Radic-Sarikas Valerie Fock Valerie Fock Veveeyan Suresh Veveeyan Suresh Maximilian Kauer Maximilian Kauer Aleksandr Bykov Aleksandr Bykov Danijela Kurija Danijela Kurija Michaela Schlederer Michaela Schlederer Lukas Kenner Lukas Kenner Gerhard Weber Gerhard Weber Wolfgang Mikulits Wolfgang Mikulits Florian Halbritter Florian Halbritter Richard Moriggl Richard Moriggl Heinrich Kovar Heinrich Kovar Cell Press 2025 Ewing sarcoma (EwS) is an aggressive cancer of adolescents in need of effective treatment. Insulin-like growth factor (IGF)-1 is an autocrine growth factor for EwS, but only 10% of patients respond to IGF-1 receptor (IGF-1R) blockade. Although EwS is presumed to originate from mesenchymal progenitors during bone development, targeting of the EwS driver oncogene EWS::FLI1 to the mesenchymal lineage in a mouse model does not result in tumor formation but in skeletal malformations and perinatal death. We report that transient exposure to IGF-1 concentrations mimicking serum levels during puberty reprograms limb-derived mesenchymal cells of EWS::FLI1-mutant mice to stable transformation and tumorigenicity. We identify a modular mechanism of IGF-1-driven tumor promotion in the early steps of EwS pathogenesis, in which Yap1 plays a central role. Pharmacologic Yap1/Tead inhibition reverses the transformed phenotype of EWS::FLI1-expressing cells. Our data provide a rationale for combined IGF-1R and YAP/TEAD inhibition in the treatment of EwS patients. PDFDocument eng 2025-04-14T08:11:57.561643Z 2025 Animals Mesenchymal Stem Cells Metabolism YAP-Signaling Proteins Metabolism RNA-Binding Protein EWS Metabolism RNA-Binding Protein EWS Genetics Humans Mice Cell Transformation, Neoplastic Metabolism Cell Transformation, Neoplastic Genetics Proto-Oncogene Protein c-fli-1Metabolism Proto-Oncogene Protein c-fli-1Genetics Adaptor Proteins, Signal Transducing Metabolism Insulin-Like Growth Factor I Metabolism Transcription Factors Metabolism Sarcoma, Ewing Metabolism Sarcoma, Ewing Pathology Sarcoma, Ewing Genetics Cellular Reprogramming Drug Effects Oncogene Proteins, Fusion Metabolism Oncogene Proteins, Fusion Genetics Receptor, IGF Type 1 Metabolism Bone and Bones Metabolism Bone and Bones Pathology 5572699 b application/pdf http://creativecommons.org/licenses/by-nc-nd/4.0/