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Marchetto, Aruna; Ohmura, Shunya; Orth, Martin F.; Knott, Maximilian M. L.; Colombo, Maria V.; Arrigoni, Chiara; Bardinet, Victor; Saucier, David; Wehweck, Fabienne S.; Li, Jing; Stein, Stefanie; Gerke, Julia S.; Baldauf, Michaela C.; Musa, Julian; Dallmayer, Marlene; Romero-Pérez, Laura; Hölting, Tilman L. B.; Amatruda, James F.; Cossarizza, Andrea; Henssen, Anton G.; Kirchner, Thomas; Moretti, Matteo; Cidre-Aranaz, Florencia; Sannino, Giuseppina;

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

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  • Medientyp: E-Artikel
  • Titel: Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma
  • Beteiligte: Marchetto, Aruna; Ohmura, Shunya; Orth, Martin F.; Knott, Maximilian M. L.; Colombo, Maria V.; Arrigoni, Chiara; Bardinet, Victor; Saucier, David; Wehweck, Fabienne S.; Li, Jing; Stein, Stefanie; Gerke, Julia S.; Baldauf, Michaela C.; Musa, Julian; Dallmayer, Marlene; Romero-Pérez, Laura; Hölting, Tilman L. B.; Amatruda, James F.; Cossarizza, Andrea; Henssen, Anton G.; Kirchner, Thomas; Moretti, Matteo; Cidre-Aranaz, Florencia; Sannino, Giuseppina;
  • Erschienen: Springer Science and Business Media LLC, 2020
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/s41467-020-16244-2
  • ISSN: 2041-1723
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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.</jats:p><jats:p>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.</jats:p><jats:p>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.</jats:p>
  • Zugangsstatus: Freier Zugang