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

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Item Type:Article
Title:Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma
Creators Name:Marchetto, A. and Ohmura, S. and Orth, M.F. and Knott, M.M.L. and Colombo, M.V. and Arrigoni, C. and Bardinet, V. and Saucier, D. and Wehweck, F.S. and Li, J. and Stein, S. and Gerke, J.S. and Baldauf, M.C. and Musa, J. and Dallmayer, M. and Romero-Pérez, L. and Hölting, T.L.B. and Amatruda, J.F. and Cossarizza, A. and Henssen, A.G. and Kirchner, T. and Moretti, M. and Cidre-Aranaz, F. and Sannino, G. and Grünewald, T.G.P.
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.
Keywords:Bone Neoplasms, Cell Proliferation, Chondrocytes, DNA Methylation, Ewing Sarcoma, Fusion Oncogene Proteins, Genetic Enhancer Elements, Gene Expression Profiling, HEK293 Cells, Hydrazines, Mesenchymal Stem Cells, Microsatellite Repeats, Mitochondria, Neoplastic Gene Expression Regulation, Oligonucleotide Array Sequence Analysis, Oncogenes, Oxidative Stress, RNA Interference, Sarcoma, SOXD Transcription Factors, Tumor Cell Line, Animals, Mice
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group
Volume:11
Number:1
Page Range:2423
Date:15 May 2020
Official Publication:https://doi.org/10.1038/s41467-020-16244-2
PubMed:View item in PubMed

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