phaidra.vetmeduni.ac.at o:4046 DOI 10.1016/j.celrep.2025.115381 YAP1 is a key regulator of EWS::FLI1-dependent malignant transformation upon IGF-1-mediated reprogramming of bone mesenchymal stem cells 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. eng 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 2025-04-14T08:11:58.163Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Noorizadeh;Rahil; FN:Rahil Noorizadeh END:VCARD BEGIN:VCARD VERSION:3.0 N:Sax;Barbara; FN:Barbara Sax END:VCARD BEGIN:VCARD VERSION:3.0 N:Javaheri;Tahereh; FN:Tahereh Javaheri X-ORCID:https://orcid.org/0000-0001-6686-5574 END:VCARD BEGIN:VCARD VERSION:3.0 N:Radic-Sarikas;Branka; FN:Branka Radic-Sarikas END:VCARD BEGIN:VCARD VERSION:3.0 N:Fock;Valerie; FN:Valerie Fock END:VCARD BEGIN:VCARD VERSION:3.0 N:Suresh;Veveeyan; FN:Veveeyan Suresh END:VCARD BEGIN:VCARD VERSION:3.0 N:Kauer;Maximilian; FN:Maximilian Kauer END:VCARD BEGIN:VCARD VERSION:3.0 N:Bykov;Aleksandr; FN:Aleksandr Bykov END:VCARD BEGIN:VCARD VERSION:3.0 N:Kurija;Danijela; FN:Danijela Kurija END:VCARD BEGIN:VCARD VERSION:3.0 N:Schlederer;Michaela; FN:Michaela Schlederer END:VCARD BEGIN:VCARD VERSION:3.0 N:Kenner;Lukas; FN:Lukas Kenner X-ORCID:https://orcid.org/0000-0003-2184-1338 END:VCARD BEGIN:VCARD VERSION:3.0 N:Weber;Gerhard; FN:Gerhard Weber END:VCARD BEGIN:VCARD VERSION:3.0 N:Mikulits;Wolfgang; FN:Wolfgang Mikulits END:VCARD BEGIN:VCARD VERSION:3.0 N:Halbritter;Florian; FN:Florian Halbritter END:VCARD BEGIN:VCARD VERSION:3.0 N:Moriggl;Richard; FN:Richard Moriggl X-ORCID:https://orcid.org/0000-0003-0918-9463 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kovar;Heinrich; FN:Heinrich Kovar END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by-nc-nd/4.0 application/pdf 5572699 https://phaidra.vetmeduni.ac.at/o:4046 https://phaidra.vetmeduni.ac.at/api/object/o:4046/thumbnail LOMv1.0 discipline