TY - JOUR T1 - The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease JF - bioRxiv DO - 10.1101/283309 SP - 283309 AU - Lindsay Kosack AU - Bettina Wingelhofer AU - Alexandra Popa AU - Bojan Vilagos AU - Anna Orlova AU - Peter Majek AU - Katja Parapatics AU - Alexander Lercher AU - Benedikt Agerer AU - Anna Ringler AU - Johanna Klughammer AU - Mark Smyth AU - Kseniya Khamina AU - Hatoon Baazim AU - David A. Rosa AU - Jisung Park AU - Patrick T. Gunning AU - Christoph Bock AU - Hannah V. Siddle AU - Stefan Kubicek AU - Elizabeth P. Murchison AU - Keiryn L. Bennett AU - Richard Moriggl AU - Andreas Bergthaler Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/04/12/283309.abstract N2 - The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). 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. ER -