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The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease

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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, Woods, GM ORCID: 0000-0001-8421-7917, Kubicek, S, Murchison, EP, Bennett, KL, Moriggl, R and Bergthaler, A 2019 , 'The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease' , Cancer Cell, vol. 35, no. 1 , pp. 125-139 , doi: 10.1016/j.ccell.2018.11.018.

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Abstract

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.

Item Type: Article
Authors/Creators:Kosack, L and Wingelhofer, B and Popa, A and Orlova, A and Agerer, B and Vilagos, B and Majek, P and Parapatics, K and Lercher, A and Ringler, A and Klughammer, J and Smyth, M and Khamina, K and Baazim, H and de Araujo, ED and Rosa, DA and Park, J and Tin, G and Ahmar, S and Gunning, PT and Bock, C and Siddle, HV and Woods, GM and Kubicek, S and Murchison, EP and Bennett, KL and Moriggl, R and Bergthaler, A
Keywords: ERBB, MHC class I, STAT3, Tasmanian devil, horizontal transmission, receptor tyrosine kinases, systems biology, transmissible cancer, tumor vulnerability, xenograft
Journal or Publication Title: Cancer Cell
Publisher: Cell Press
ISSN: 1535-6108
DOI / ID Number: 10.1016/j.ccell.2018.11.018
Copyright Information:

Copyright 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/

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