Artículo
Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma
Autor/es | Marchetto, Aruna
Ohmura, Shunya Orth, Martin F. Knott, Maximilian M.L. Colombo, Maria V. Romero Pérez, Laura ![]() ![]() ![]() ![]() ![]() ![]() |
Departamento | Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica |
Fecha de publicación | 2020 |
Fecha de depósito | 2023-06-15 |
Publicado en |
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Resumen | 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 ... 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 tar- geted therapy. |
Cita | Marchetto, A., Ohmura, S., Orth, M.F., Knott, M.M.L., Colombo, M.V. y Romero Pérez, L. (2020). Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma. Nature Communications, 11 (1), 1-16. https://doi.org/10.1038/s41467-020-16244-2. |