The Tasmanian devil faces extinction due to devil facial tumor disease (DFTD), which is transmitted between individuals by bites during fighting. Cancer cells do not usually transmit between individuals. To unveil the molecular underpinnings of DFTD, we designed an approach that combines sensitivity to drugs with an integrated systems-biology characterization. Sensitivity to inhibitors of the ERBB family of receptor tyrosine kinases correlated with their overexpression, suggesting a causative link. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to oncogenic signaling hubs including evolutionary conserved STAT3. Indeed, ERBB inhibition blocked phosphorylation of STAT3 and arrested cancer cells. Pharmacological blockade of ERBB signaling prevented tumor growth in a xenograft model and resulted in recovery of MHC class I gene expression. This link between the hyperactive ERBB-STAT3 axis and MHC class I mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and led us to the proposition of a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD. While pharmacological treatments come with inherent logistic limitations for wildlife diseases, this rationalized therapeutic strategy – possibly in combination with a vaccine against DFTD and/or immunotherapeutic interventions- offers a much-needed expansion of the so far limited measures to preserve the Tasmanian devil from extinction.
The manuscript of this landmark study has now become available on Bioarchives.
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