Journal
CANCER CELL
Volume 35, Issue 1, Pages 125-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.11.018
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Funding
- Austrian Academy of Sciences
- Austrian Science Fund (FWF) [DK W1212]
- European Research Council (ERC) under the European Union's Seventh Framework Program and Horizon 2020 research and innovation program [677006]
- FWF [SFB F4707-B20, SFB-F06105]
- Austrian Research Promotion Agency (FFG) [854452]
- Austrian Science Fund (FWF) [W1212] Funding Source: Austrian Science Fund (FWF)
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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.
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