YAP1 is a key regulator of EWS::FLI1-dependent malignant transformation upon IGF-1-mediated reprogramming of bone mesenchymal stem cells

• DOI: 10.1016/j.celrep.2025.115381
• Publication Date: 2025-03-12T01:06:02Z
• Authors: Rahil Noorizadeh; Barbara Sax; Tahereh Javaheri; Branka Radic-Sarikas; Valerie Fock; Veveeyan Suresh; Maximilian Kauer; Aleksandr Bykov; Danijela Kurija; Michaela Schlederer; Lukas Kenner; Gerhard Weber; Wolfgang Mikulits; Florian Halbritter; Richard Moriggl; Heinrich Kovar
• Keywords: Reprogramming; YAP1

Ewing sarcoma (EwS) is an aggressive cancer of adolescents in need effective treatment. Insulin-like growth factor (IGF)-1 autocrine for EwS, but only 10% patients respond to IGF-1 receptor (IGF-1R) blockade. Although EwS presumed originate from mesenchymal progenitors during bone development, targeting the driver oncogene EWS::FLI1 lineage a mouse model does not result tumor formation skeletal malformations and perinatal death. We report that transient exposure concentrations mimicking serum levels puberty reprograms limb-derived cells EWS::FLI1-mutant mice stable transformation tumorigenicity. identify modular mechanism IGF-1-driven promotion early steps pathogenesis, which Yap1 plays central role. Pharmacologic Yap1/Tead inhibition reverses transformed phenotype EWS::FLI1-expressing cells. Our data provide rationale combined IGF-1R YAP/TEAD treatment patients.