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

  • Marchetto A Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Ohmura S Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Orth MF Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Knott MML Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Colombo MV Regenerative Medicine Technologies Laboratory, Ente Ospedaliero Cantonale (EOC), Lugano, Switzerland.
  • Arrigoni C Regenerative Medicine Technologies Laboratory, Ente Ospedaliero Cantonale (EOC), Lugano, Switzerland.
  • Bardinet V Department of Pediatrics, Division of Oncology and Hematology, Charité Berlin, Berlin, Germany.
  • Saucier D Department of Pediatrics and Molecular Biology, University of Texas Southwestern Medical Center and Children's Medical Center, Dallas, TX, USA.
  • Wehweck FS Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Li J Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Stein S Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Gerke JS Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Baldauf MC Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Musa J Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Dallmayer M Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Romero-Pérez L Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Hölting TLB Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Amatruda JF Department of Pediatrics and Molecular Biology, University of Texas Southwestern Medical Center and Children's Medical Center, Dallas, TX, USA.
  • Cossarizza A Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy.
  • Henssen AG Department of Pediatrics, Division of Oncology and Hematology, Charité Berlin, Berlin, Germany.
  • Kirchner T Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Moretti M Regenerative Medicine Technologies Laboratory, Ente Ospedaliero Cantonale (EOC), Lugano, Switzerland.
  • Cidre-Aranaz F Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Sannino G Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Grünewald TGP Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. t.gruenewald@dkfz-heidelberg.de.
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  • 2020-05-17
Published in:
  • Nature communications. - 2020
Adult
Animals
Bone Neoplasms
Cell Line, Tumor
Cell Proliferation
Child
Chondrocytes
DNA Methylation
Enhancer Elements, Genetic
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Hydrazines
Mesenchymal Stem Cells
Mice
Microsatellite Repeats
Mitochondria
Oligonucleotide Array Sequence Analysis
Oncogene Proteins, Fusion
Oncogenes
Oxidative Stress
RNA Interference
SOXD Transcription Factors
Sarcoma
Sarcoma, Ewing
English 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.
Language
  • English
Open access status
gold
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Persistent URL
https://sonar.ch/global/documents/177505
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