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

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-Perez, Laura; Hoelting, Tilman L. B.; Amatruda, James F.; Cossarizza, Andrea; Henssen, Anton G.; Kirchner, Thomas; Moretti, Matteo; Cidre-Aranaz, Florencia; Sannino, Giuseppina und Grünewald, Thomas G. P. (2020): Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma. In: Nature Communications, Bd. 11, Nr. 1, 2423

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. Ewing sarcoma is characterized by the fusion of EWSR1 and FLI1. Here, the authors show that EWSR1-FLI1 increases the activity of the developmental transcription factor SOX6, which promotes tumor growth but also increases sensitivity to oxidative stress.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2041-1723
• Sprache: Englisch