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Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma

Author

Listed:
  • Aruna Marchetto

    (LMU Munich)

  • Shunya Ohmura

    (LMU Munich)

  • Martin F. Orth

    (LMU Munich)

  • Maximilian M. L. Knott

    (LMU Munich
    LMU Munich)

  • Maria V. Colombo

    (Ente Ospedaliero Cantonale (EOC))

  • Chiara Arrigoni

    (Ente Ospedaliero Cantonale (EOC))

  • Victor Bardinet

    (Division of Oncology and Hematology, Charité Berlin)

  • David Saucier

    (University of Texas Southwestern Medical Center and Children’s Medical Center)

  • Fabienne S. Wehweck

    (LMU Munich
    LMU Munich)

  • Jing Li

    (LMU Munich)

  • Stefanie Stein

    (LMU Munich)

  • Julia S. Gerke

    (LMU Munich)

  • Michaela C. Baldauf

    (LMU Munich)

  • Julian Musa

    (LMU Munich
    University of Heidelberg)

  • Marlene Dallmayer

    (LMU Munich)

  • Laura Romero-Pérez

    (LMU Munich
    Hopp-Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Tilman L. B. Hölting

    (LMU Munich)

  • James F. Amatruda

    (University of Texas Southwestern Medical Center and Children’s Medical Center
    Children’s Hospital of Los Angeles)

  • Andrea Cossarizza

    (University of Modena and Reggio Emilia School of Medicine)

  • Anton G. Henssen

    (Division of Oncology and Hematology, Charité Berlin
    Berlin Institute of Health
    Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
    German Cancer Consortium (DKTK), partner site)

  • Thomas Kirchner

    (LMU Munich
    German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK), partner site)

  • Matteo Moretti

    (Ente Ospedaliero Cantonale (EOC))

  • Florencia Cidre-Aranaz

    (LMU Munich
    Hopp-Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Giuseppina Sannino

    (LMU Munich)

  • Thomas G. P. Grünewald

    (LMU Munich
    LMU Munich
    Hopp-Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

Abstract

Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers. Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 – a physiological driver of proliferation of osteo-chondrogenic progenitors – by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol. Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.

Suggested Citation

  • Aruna Marchetto & Shunya Ohmura & Martin F. Orth & Maximilian M. L. Knott & Maria V. Colombo & Chiara Arrigoni & Victor Bardinet & David Saucier & Fabienne S. Wehweck & Jing Li & Stefanie Stein & Juli, 2020. "Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16244-2
    DOI: 10.1038/s41467-020-16244-2
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    Cited by:

    1. Yong Ryoul Kim & Jaegeon Joo & Hee Jung Lee & Chaelim Kim & Ju-Chan Park & Young Suk Yu & Chang Rok Kim & Do Hui Lee & Joowon Cha & Hyemin Kwon & Kimberley M. Hanssen & Thomas G. P. Grünewald & Murim , 2024. "Prion-like domain mediated phase separation of ARID1A promotes oncogenic potential of Ewing’s sarcoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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