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

  • Cell Rep. 2025 Mar 25;44(3):115381. doi: 10.1016/j.celrep.2025.115381.
Rahil Noorizadeh  1 ,  Barbara Sax  2 ,  Tahereh Javaheri  2 ,  Branka Radic-Sarikas  3 ,  Valerie Fock  4 ,  Veveeyan Suresh  4 ,  Maximilian Kauer  4 ,  Aleksandr Bykov  4 ,  Danijela Kurija  5 ,  Michaela Schlederer  6 ,  Lukas Kenner  7 ,  Gerhard Weber  8 ,  Wolfgang Mikulits  8 ,  Florian Halbritter  4 ,  Richard Moriggl  9 ,  Heinrich Kovar  10
Affiliations
  • 1. St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
  • 2. Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria.
  • 3. St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria; Department of Pediatric Surgery, Medical University of Vienna, 1090 Vienna, Austria.
  • 4. St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria.
  • 5. Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria.
  • 6. Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria; Department of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, 1090 Vienna, Austria.
  • 7. Department of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, 1090 Vienna, Austria; Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; Christian Doppler Laboratory for Applied Metabolomics, Medical University of Vienna, 1090 Vienna, Austria; Center for Biomarker Research in Medicine (CBmed), 8010 Graz, Austria.
  • 8. Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
  • 9. Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria; Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, 5020 Salzburg, Austria; Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
  • 10. St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria; Department of Pediatrics, Medical University of Vienna, 1090 Vienna, Austria. Electronic address: [email protected].
PMID: 40080499 DOI: 10.1016/j.celrep.2025.115381
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.

Keywords
CP: Stem cell research; EWS::FLI1; Ewing sarcoma; IGF-1/insulin signaling; YAP1/TAZ signaling; endochondral bone development; mesenchymal stem cells; puberty.
Products