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

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

Cancer cell (2019-01-16)

Lindsay Kosack, Bettina Wingelhofer, Alexandra Popa, Anna Orlova, Benedikt Agerer, Bojan Vilagos, Peter Majek, Katja Parapatics, Alexander Lercher, Anna Ringler, Johanna Klughammer, Mark Smyth, Kseniya Khamina, Hatoon Baazim, Elvin D de Araujo, David A Rosa, Jisung Park, Gary Tin, Siawash Ahmar, Patrick T Gunning, Christoph Bock, Hannah V Siddle, Gregory M Woods, Stefan Kubicek, Elizabeth P Murchison, Keiryn L Bennett, Richard Moriggl, Andreas Bergthaler

PMID30645971

摘要

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.