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

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

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: heinrich.kovar@ccri.at.
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.

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