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

Author

Listed:
  • Inmaculada Hernández-Muñoz

    (Hospital del Mar Research Institute
    Institut de Recerca Sant Joan de Déu)

  • Irene Cuervas

    (Hospital del Mar Research Institute
    Institut de Recerca Sant Joan de Déu)

  • Estela Prada

    (Institut de Recerca Sant Joan de Déu)

  • Julian Pulecio

    (Bellvitge Biomedical Research Institute (IDIBELL)
    Sloan Kettering Institute)

  • 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)
    Program for Clinical Translation of Regenerative Medicine in Catalonia (P-[CMRC])
    Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN))

  • Enrique Vidal

    (The Barcelona Institute of Science and Technology
    Health Research Institute Hospital La Fe
    Health Research Institute Hospital La Fe)

  • 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
    Hospital Sant Joan de Déu)

  • Angel Raya

    (Bellvitge Biomedical Research Institute (IDIBELL)
    Institució Catalana de Recerca i Estudis Avançats (ICREA)
    University of Barcelona)

  • Jaume Mora

    (Institut de Recerca Sant Joan de Déu
    Hospital Sant Joan de Déu)

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.

Suggested Citation

  • 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 , 2025. "EWS::FLI1 expression in human embryonic mesenchymal stem cells leads to transcriptional reprograming, defective DNA damage repair and Ewing sarcoma," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64475-y
    DOI: 10.1038/s41467-025-64475-y
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    References listed on IDEAS

    as
    1. Aparna Gorthi & July Carolina Romero & Eva Loranc & Lin Cao & Liesl A. Lawrence & Elicia Goodale & Amanda Balboni Iniguez & Xavier Bernard & V. Pragathi Masamsetti & Sydney Roston & Elizabeth R. Lawlo, 2018. "EWS–FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma," Nature, Nature, vol. 555(7696), pages 387-391, March.
    Full references (including those not matched with items on IDEAS)

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