Nature communications, 2020-05, Vol.11 (1), p.2423-2423, Article 2423
- 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-Pérez, Laura
- Hölting, Tilman L B
- Amatruda, James F
- Cossarizza, Andrea
- Henssen, Anton G
- Kirchner, Thomas
- Moretti, Matteo
- Cidre-Aranaz, Florencia
- Sannino, Giuseppina
- Grünewald, Thomas G P
2020
Details
- Autor(en) / Beteiligte
- 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-Pérez, Laura
- Hölting, Tilman L B
- Amatruda, James F
- Cossarizza, Andrea
- Henssen, Anton G
- Kirchner, Thomas
- Moretti, Matteo
- Cidre-Aranaz, Florencia
- Sannino, Giuseppina
- Grünewald, Thomas G P
- Titel
- Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma
- Ist Teil von
- Nature communications, 2020-05, Vol.11 (1), p.2423-2423, Article 2423
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2020
- Link zum Volltext
- Quelle
- Elektronische Zeitschriftenbibliothek (Open access)
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-020-16244-2Titel-ID: cdi_doaj_primary_oai_doaj_org_article_6dc51a99a4e44ac186061ab97fa34c62
- Format
- –
- Schlagworte
- Adult, Animals, Biomedical materials, Bone Neoplasms - pathology, Cell Line, Tumor, Cell Proliferation, Child, Children, Chondrocytes - metabolism, DNA Methylation, Enhancer Elements, Genetic, Enhancers, ETS protein, Ewing's sarcoma, Ewings sarcoma, FLI-1 protein, Gene expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Hydrazines - chemistry, Malignancy, Mesenchymal Stem Cells - metabolism, Mesenchyme, Mice, Microsatellite Repeats, Microsatellites, Mitochondria - metabolism, Oligonucleotide Array Sequence Analysis, Oncogene Proteins, Fusion - metabolism, Oncogenes, Osteoprogenitor cells, Oxidative Stress, Physiological effects, RNA Interference, Sarcoma, Sarcoma - genetics, Sarcoma, Ewing - pathology, SOXD Transcription Factors - metabolism, Stem cells, Three dimensional models, Transcription activation, Transcription factors