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

Adult Animals Bone Neoplasms / pathology Cell Line, Tumor Cell Proliferation Child Chondrocytes / metabolism DNA Methylation Enhancer Elements, Genetic Gene Expression Profiling Gene Expression Regulation, Neoplastic HEK293 Cells Humans Hydrazines / chemistry Mesenchymal Stem Cells / metabolism Mice Microsatellite Repeats Mitochondria / metabolism Oligonucleotide Array Sequence Analysis Oncogene Proteins, Fusion / metabolism Oncogenes Oxidative Stress RNA Interference SOXD Transcription Factors / metabolism Sarcoma / genetics Sarcoma, Ewing / pathology

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
15 05 2020
Historique:
received: 21 03 2019
accepted: 23 04 2020
entrez: 17 5 2020
pubmed: 18 5 2020
medline: 25 8 2020
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-020-16244-2 PMID: 32415069 PMC: PMC7228971
pubmed: 32415069
doi: 10.1038/s41467-020-16244-2
pii: 10.1038/s41467-020-16244-2
pmc: PMC7228971
doi:

Substances chimiques

EWSR1-FLI1 fusion protein, human 0
Hydrazines 0
Oncogene Proteins, Fusion 0
SOX6 protein, human 0
SOXD Transcription Factors 0
elesclomol 6UK191M53P

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

2423

Subventions

Organisme : NCI NIH HHS
ID : F31 CA236410
Pays : United States

Commentaires et corrections

Type : ErratumIn

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Auteurs

Aruna Marchetto (A)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
ORCID: 0000-0002-8873-2251

Shunya Ohmura (S)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
ORCID: 0000-0002-0930-5172

Martin F Orth (MF)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
ORCID: 0000-0002-1789-6427

Maximilian M L Knott (MML)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
ORCID: 0000-0002-6995-3702

Maria V Colombo (MV)

Regenerative Medicine Technologies Laboratory, Ente Ospedaliero Cantonale (EOC), Lugano, Switzerland.
ORCID: 0000-0002-6018-9920

Chiara Arrigoni (C)

Regenerative Medicine Technologies Laboratory, Ente Ospedaliero Cantonale (EOC), Lugano, Switzerland.
ORCID: 0000-0001-6808-1642

Victor Bardinet (V)

Department of Pediatrics, Division of Oncology and Hematology, Charité Berlin, Berlin, Germany.

David Saucier (D)

Department of Pediatrics and Molecular Biology, University of Texas Southwestern Medical Center and Children's Medical Center, Dallas, TX, USA.
ORCID: 0000-0001-8484-198X

Fabienne S Wehweck (FS)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.

Jing Li (J)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.

Stefanie Stein (S)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.

Julia S Gerke (JS)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.

Michaela C Baldauf (MC)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.

Julian Musa (J)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
ORCID: 0000-0002-9138-1819

Marlene Dallmayer (M)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.

Laura Romero-Pérez (L)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany.
Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
ORCID: 0000-0003-3196-4382

Tilman L B Hölting (TLB)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
ORCID: 0000-0001-5598-7330

James F Amatruda (JF)

Department of Pediatrics and Molecular Biology, University of Texas Southwestern Medical Center and Children's Medical Center, Dallas, TX, USA.
Children's Hospital of Los Angeles, Los Angeles, CA, USA.
ORCID: 0000-0002-9901-2137

Andrea Cossarizza (A)

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy.
ORCID: 0000-0002-5381-1558

Anton G Henssen (AG)

Department of Pediatrics, Division of Oncology and Hematology, Charité Berlin, Berlin, Germany.
Berlin Institute of Health, Berlin, Germany.
Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, Berlin, Germany.
German Cancer Consortium (DKTK), partner site, Berlin, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
ORCID: 0000-0003-1534-778X

Thomas Kirchner (T)

Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
German Cancer Consortium (DKTK), partner site, Munich, Germany.

Matteo Moretti (M)

Regenerative Medicine Technologies Laboratory, Ente Ospedaliero Cantonale (EOC), Lugano, Switzerland.

Florencia Cidre-Aranaz (F)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany.
Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
ORCID: 0000-0002-0246-7179

Giuseppina Sannino (G)

Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.

Thomas G P 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.
Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. t.gruenewald@dkfz-heidelberg.de.
Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany. t.gruenewald@dkfz-heidelberg.de.
Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. t.gruenewald@dkfz-heidelberg.de.
German Cancer Consortium (DKTK), partner site, Munich, Germany. t.gruenewald@dkfz-heidelberg.de.
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. t.gruenewald@dkfz-heidelberg.de.
ORCID: 0000-0003-0920-7377

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Oncogenic hijacking of a developmental...
questionsmedicales.fr › Eucaryotes › Animaux › Oncogenic hijacking of a developmental...
questionsmedicales.fr › Maladies ostéomusculaires › Maladies osseuses › Tumeurs osseuses › Oncogenic hijacking of a developmental...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Oncogenic hijacking of a developmental...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Oncogenic hijacking of a developmental...
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