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

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

doi:10.1016/j.celrep.2025.115381

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Title (eng)

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

Author

Rahil Noorizadeh

Barbara Sax

Tahereh Javaheri

Branka Radic-Sarikas

Valerie Fock

Veveeyan Suresh

Maximilian Kauer

Aleksandr Bykov

Danijela Kurija

Michaela Schlederer

Lukas Kenner

University of Veterinary Medicine Vienna

Gerhard Weber

Wolfgang Mikulits

Florian Halbritter

Richard Moriggl

University of Veterinary Medicine Vienna

Heinrich Kovar

Abstract (eng)

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.

Keywords (eng)

AnimalsMesenchymal Stem Cells MetabolismYAP-Signaling Proteins MetabolismRNA-Binding Protein EWS MetabolismRNA-Binding Protein EWS GeneticsHumansMiceCell Transformation, Neoplastic MetabolismCell Transformation, Neoplastic GeneticsProto-Oncogene Protein c-fli-1MetabolismProto-Oncogene Protein c-fli-1GeneticsAdaptor Proteins, Signal Transducing MetabolismInsulin-Like Growth Factor I MetabolismTranscription Factors MetabolismSarcoma, Ewing MetabolismSarcoma, Ewing PathologySarcoma, Ewing GeneticsCellular Reprogramming Drug EffectsOncogene Proteins, Fusion MetabolismOncogene Proteins, Fusion GeneticsReceptor, IGF Type 1 MetabolismBone and Bones MetabolismBone and Bones Pathology

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4046

DOI

10.1016/j.celrep.2025.115381

Is in series

Title (eng)

Cell Reports

Volume