Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Noorizadeh, R; Sax, B; Javaheri, T; Radic-Sarikas, B; Fock, V; Suresh, V; Kauer, M; Bykov, A; Kurija, D; Schlederer, M; Kenner, L; Weber, G; Mikulits, W; Halbritter, F; Moriggl, R; Kovar, H; Mikulits, W; Halbritter, F; Moriggl, R; Kovar, H.
YAP1 is a key regulator of EWS::FLI1-dependent malignant transformation upon IGF-1-mediated reprogramming of bone mesenchymal stem cells
CELL REP. 2025; 44(3): 115381 Doi: 10.1016/j.celrep.2025.115381 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

 

Co-authors Med Uni Graz

Kenner Lukas

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Abstract:

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.

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