YAP1 is a key regulator of EWS::FLI1-dependent malignant transformation upon IGF-1-mediated reprogramming of bone mesenchymal stem cells
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.
Authors
- Florian Halbritter (ORCID: https://orcid.org/0000-0003-2452-4784)
- Richard Moriggl (ORCID: https://orcid.org/0000-0003-0918-9463)
- Branka Radic-Sarikas (ORCID: https://orcid.org/0000-0002-3597-0483)
- Michaela Schlederer
- Aleksandr Bykov (ORCID: https://orcid.org/0000-0003-4532-9865)
- Heinrich Kovar (ORCID: https://orcid.org/0000-0001-6873-9109)
- Tahereh Javaheri (ORCID: https://orcid.org/0000-0001-6686-5574)
- Veveeyan Suresh (ORCID: https://orcid.org/0000-0003-3318-8030)
- Lukas Kenner (ORCID: https://orcid.org/0000-0003-2184-1338)
- Valerie Fock (ORCID: https://orcid.org/0000-0002-7812-4340)
- Wolfgang Mikulits (ORCID: https://orcid.org/0000-0003-4612-7106)
- Rahil Noorizadeh
- Barbara Sax
- Maximilian Kauer
- Gerhard Weber
- Danijela Kurija
Institutions
- University of Salzburg (AT)
- Comprehensive Cancer Center Vienna (AT)
- St Anna Children's Hospital (AT)
- Ludwig Boltzmann Institute for Cancer Research (AT)
- St. Anna Children's Cancer Research Institute
- Community College of Rhode Island (US)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115381
- Citations
- 6
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 6.91
Funders
- Alex's Lemonade Stand Foundation for Childhood Cancer
- European Commission
- Austrian Science Fund
- Horizon 2020 Framework Programme