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

Publication

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

Journal Paper/Review - May 15, 2020

Marchetto Aruna, 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, Musa Julian, Baldauf Michaela, Gerke Julia S, 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, Grünewald Thomas G P

Citation

Marchetto A, Dallmayer M, Romero-Pérez L, Hölting T, Amatruda J, Cossarizza A, Henssen A, Kirchner T, Moretti M, Cidre-Aranaz F, Sannino G, Musa J, Baldauf M, Gerke J, Ohmura S, Orth M, Knott M, Colombo M, Arrigoni C, Bardinet V, Saucier D, Wehweck F, Li J, Stein S, Grünewald T. Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma. Nat Commun 2020; 11:2423.

Type

Journal Paper/Review (English)

Journal

Nat Commun 2020; 11

Publication Date

May 15, 2020

Issn Electronic

2041-1723

Pages

2423

Brief description/objective

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.