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

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, Julia S. Gerke, Michaela C. Baldauf, Julian Musa, Marlene Dallmayer, Laura Romero-Pérez, Tilman L. B. Hölting, James F. Amatruda, Andrea Cossarizza, Anton G. Henssen, Thomas Kirchner, Matteo Moretti, Florencia Cidre-Aranaz, Giuseppina Sannino and Thomas G. P. Grünewald ()
Additional contact information
Aruna Marchetto: LMU Munich
Shunya Ohmura: LMU Munich
Martin F. Orth: LMU Munich
Maximilian M. L. Knott: 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
Jing Li: LMU Munich
Stefanie Stein: LMU Munich
Julia S. Gerke: LMU Munich
Michaela C. Baldauf: LMU Munich
Julian Musa: LMU Munich
Marlene Dallmayer: LMU Munich
Laura Romero-Pérez: LMU Munich
Tilman L. B. Hölting: LMU Munich
James F. Amatruda: University of Texas Southwestern Medical Center and Children’s Medical Center
Andrea Cossarizza: University of Modena and Reggio Emilia School of Medicine
Anton G. Henssen: Division of Oncology and Hematology, Charité Berlin
Thomas Kirchner: LMU Munich
Matteo Moretti: Ente Ospedaliero Cantonale (EOC)
Florencia Cidre-Aranaz: LMU Munich
Giuseppina Sannino: LMU Munich
Thomas G. P. Grünewald: LMU Munich

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-020-16244-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16244-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-16244-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().