Zeitschriftenaufsatz
|
2025
YAP1 is a key regulator of EWS::FLI1-dependent malignant transformation upon IGF-1-mediated reprogramming of bone mesenchymal stem cells
Autor:in
Noorizadeh, Rahil; Sax, Barbara; Javaheri, Tahereh; Sarikas, Branka Radic; Fock, Valerie; Suresh, Veveeyan; Kauer, Maximilian; Bykov, Aleksandr; Kurija, Danijela; Schlederer, Michaela; Kenner, Lukas; Weber, Gerhard W.; Mikulits, Wolfgang; Halbritter, Florian; Moriggl, Richard; Kovar, Heinrich; Mikulits, Wolfgang; Halbritter, Florian; Moriggl, Richard; Kovar, Heinrich
Publikationen als Autor:in / Herausgeber:in der Vetmeduni
Journal
Abstrakt
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.
Schlagwörter
Animals; Mesenchymal Stem Cellsmetabolism; YAP-Signaling Proteinsmetabolism; RNA-Binding Protein EWSmetabolismgenetics; Humans; Mice; Cell Transformation, Neoplasticmetabolismgenetics; Proto-Oncogene Protein c-fli-1metabolismgenetics; Adaptor Proteins, Signal Transducingmetabolism; Insulin-Like Growth Factor Imetabolism; Transcription Factorsmetabolism; Sarcoma, Ewingmetabolismpathologygenetics; Cellular Reprogrammingdrug effects; Oncogene Proteins, Fusionmetabolismgenetics; Receptor, IGF Type 1metabolism; Bone and Bonesmetabolismpathology
Dokumententyp
Originalarbeit
CC Lizenz
CCBYNCND
Open Access Type
Gold
ISSN/eISSN
2211-1247 -
10.1016/j.celrep.2025.115381
WoS ID
PubMed ID
Repository Phaidra