EWS::FLI1 expression in human embryonic mesenchymal stem cells leads to transcriptional reprograming, defective DNA damage repair and Ewing sarcoma

Inmaculada Hernández-Muñoz (), Irene Cuervas, Estela Prada, Julian Pulecio, Ramón Gimeno, Evelyn Andrades, Soledad Gómez-González, Pau Berenguer-Molins, Ariadna Acedo-Terrades, Júlia Perera-Bel, Marta Bódalo-Torruella, Lara Nonell, Elena Pérez, Daniela Grases, Caterina Mata, José Yélamos, Yvonne Richaud-Patin, Enrique Vidal, Yasmina Cuartero, François Dily, Mariona Suñol, Alejandro Manzanares, Angel Raya and Jaume Mora ()
Additional contact information
Inmaculada Hernández-Muñoz: Hospital del Mar Research Institute
Irene Cuervas: Hospital del Mar Research Institute
Estela Prada: Institut de Recerca Sant Joan de Déu
Julian Pulecio: Bellvitge Biomedical Research Institute (IDIBELL)
Ramón Gimeno: Hospital del Mar
Evelyn Andrades: Hospital del Mar Research Institute
Soledad Gómez-González: Institut de Recerca Sant Joan de Déu
Pau Berenguer-Molins: Hospital del Mar Research Institute (HMRIB)
Ariadna Acedo-Terrades: Hospital del Mar Research Institute (HMRIB)
Júlia Perera-Bel: Hospital del Mar Research Institute (HMRIB)
Marta Bódalo-Torruella: Hospital del Mar Research Institute (HMRIB)
Lara Nonell: Vall d’Hebron Institute of Oncology (VHIO)
Elena Pérez: Josep Carreras Leukaemia Research Institute (IJC)
Daniela Grases: Josep Carreras Leukaemia Research Institute (IJC)
Caterina Mata: Josep Carreras Leukaemia Research Institute (IJC)
José Yélamos: Hospital del Mar
Yvonne Richaud-Patin: Bellvitge Biomedical Research Institute (IDIBELL)
Enrique Vidal: The Barcelona Institute of Science and Technology
Yasmina Cuartero: The Barcelona Institute of Science and Technology
François Dily: The Barcelona Institute of Science and Technology
Mariona Suñol: Hospital Sant Joan de Déu
Alejandro Manzanares: Institut de Recerca Sant Joan de Déu
Angel Raya: Bellvitge Biomedical Research Institute (IDIBELL)
Jaume Mora: Institut de Recerca Sant Joan de Déu

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64475-y

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