EWS::FLI1 expression in human embryonic mesenchymal stem cells leads to transcriptional reprograming, defective DNA damage repair and Ewing sarcoma
Ewing sarcoma (ES) is an aggressive bone and soft tissue neoplasm characterized by EWSR::ETS rearrangements whose cellular origin remains unclear. EWS::FLI1 expression in human pediatric mesenchymal stem cells (MSCs) induces a transcriptional response distinct from that of human adult MSCs, but fails to form tumors. Here we show that EWS::FLI1 expression in human embryonic mesenchymal stem cells (heMSCs) results in the acquisition of an ES transcriptome, with the oncogene not preferentially binding to gene promoters, but to intronic and intergenic microsatellites. In heMSCs, EWS::FLI1 directly regulates the expression of the DNA repair protein BRCA1, although cells expressing EWS::FLI1 show DNA damage. Xenografting of EWS::FLI1-transduced heMSCs results in the formation of tumors expressing characteristic ES markers. In summary, we show that EWS::FLI1 enforces an aberrant transcriptome and solely is able to endow transforming capacity when expressed in undifferentiated, early heMSCs.
Authors
- Ramón Gimeno (ORCID: https://orcid.org/0000-0002-8758-121X)
- Yvonne Richaud‐Patín
- Elena Pérez
- Inmaculada Hernández‐Muñoz (ORCID: https://orcid.org/0000-0003-3436-9634)
- Caterina Mata (ORCID: https://orcid.org/0000-0001-9403-7434)
- Evelyn Andrades (ORCID: https://orcid.org/0000-0003-2166-6760)
- José Yélamos (ORCID: https://orcid.org/0000-0003-1195-1496)
- François Le Dily (ORCID: https://orcid.org/0000-0002-8324-7927)
- Marta Bódalo‐Torruella (ORCID: https://orcid.org/0000-0002-5950-4700)
- Daniela Grases (ORCID: https://orcid.org/0000-0002-5981-7248)
- Mariona Suñol (ORCID: https://orcid.org/0000-0002-8054-9698)
- Alejandro Manzanares (ORCID: https://orcid.org/0000-0001-9268-8188)
- Lara Nonell (ORCID: https://orcid.org/0000-0002-8538-8213)
- Soledad Gómez‐González (ORCID: https://orcid.org/0000-0002-0578-4276)
- Júlia Perera‐Bel (ORCID: https://orcid.org/0000-0002-6809-132X)
- Jaume Mora (ORCID: https://orcid.org/0000-0002-9386-5980)
- Yasmina Cuartero (ORCID: https://orcid.org/0000-0001-8611-2246)
- Julián Pulecio (ORCID: https://orcid.org/0000-0002-4455-8095)
- Ángel Raya (ORCID: https://orcid.org/0000-0003-2189-9775)
- Estela Prada (ORCID: https://orcid.org/0000-0003-4611-1120)
- Ariadna Acedo-Terrades (ORCID: https://orcid.org/0009-0009-3222-7086)
- Pau Berenguer‐Molins (ORCID: https://orcid.org/0000-0002-0170-2931)
- Enrique Vidal (ORCID: https://orcid.org/0000-0002-4217-1807)
- Irene Cuervas
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Hospital Sant Joan de Déu Barcelona (ES)
- Kettering University (US)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (ES)
- Ajuntament de L’Hospitalet (ES)
- Leitat Technological Center (ES)
- Sant Joan de Déu Research Foundation (ES)
- Hospital Del Mar (ES)
- Centre for Genomic Regulation (ES)
- Center of Regenerative Medicine in Barcelona (ES)
- Instituto de Investigación Sanitaria La Fe (ES)
- Vall d'Hebron Institute of Oncology (ES)
- Institut de Recerca Sant Joan de Déu
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-24
- DOI
- https://doi.org/10.1038/s41467-025-64475-y
- Citations
- 1
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.81