The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease.

Animals DNA Methylation Drug Screening Assays, Antitumor ErbB Receptors / metabolism Facial Neoplasms / drug therapy Gene Expression Regulation, Neoplastic / drug effects Histocompatibility Antigens Class I / metabolism Marsupialia Mice Phosphorylation Proteomics / methods STAT3 Transcription Factor / metabolism Signal Transduction Small Molecule Libraries / administration & dosage Xenograft Model Antitumor Assays

ERBB MHC class I STAT3 Tasmanian devil horizontal transmission receptor tyrosine kinases systems biology transmissible cancer tumor vulnerability xenograft

Journal

Cancer cell

ISSN: 1878-3686

Titre abrégé: Cancer Cell

Pays: United States

ID NLM: 101130617

Informations de publication

Date de publication:
14 01 2019

Historique:

received: 15 03 2018

revised: 05 10 2018

accepted: 29 11 2018

entrez: 16 1 2019

pubmed: 16 1 2019

medline: 19 10 2019

Statut: ppublish

Résumé

The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the molecular underpinnings of this transmissible cancer, we combined pharmacological screens with an integrated systems-biology characterization. Sensitivity to inhibitors of ERBB tyrosine kinases correlated with their overexpression. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to the evolutionary conserved oncogenic STAT3. ERBB inhibition blocked phosphorylation of STAT3 and arrested cancer cells. Pharmacological blockade of ERBB or STAT3 prevented tumor growth in xenograft models and restored MHC class I expression. This link between the hyperactive ERBB-STAT3 axis and major histocompatibility complex class I-mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and puts forward a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD. VIDEO ABSTRACT.

Identifiants

DOI: 10.1016/j.ccell.2018.11.018 PMID: 30645971 PMC: PMC6335503

pubmed: 30645971

pii: S1535-6108(18)30539-7

doi: 10.1016/j.ccell.2018.11.018

pmc: PMC6335503

pii:

doi:

Substances chimiques

Histocompatibility Antigens Class I 0

STAT3 Transcription Factor 0

Small Molecule Libraries 0

ErbB Receptors EC 2.7.10.1

Types de publication

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

Langues

eng

Sous-ensembles de citation

Pagination

125-139.e9

Commentaires et corrections

Type : CommentIn

Informations de copyright

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