131190 - The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease.pdf (7.77 MB)
The ERBB-STAT3 axis drives Tasmanian devil facial tumor disease
journal contributionposted on 2023-05-20, 01:29 authored by Kosack, L, Wingelhofer, B, Popa, A, Orlova, A, Agerer, B, Vilagos, B, Majek, P, Parapatics, K, Lercher, A, Ringler, A, Klughammer, J, Smyth, M, Khamina, K, Baazim, H, de Araujo, ED, Rosa, DA, Park, J, Tin, G, Ahmar, S, Gunning, PT, Bock, C, Siddle, HV, Gregory WoodsGregory Woods, Kubicek, S, Murchison, EP, Bennett, KL, Moriggl, R, Bergthaler, A
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.
Publication titleCancer Cell
Department/SchoolMenzies Institute for Medical Research
Place of publication1100 Massachusetts Ave, Cambridge, USA, Ma, 02138
Rights statementCopyright 2018 The Authors. Published by Elsevier Inc. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/