TY - JOUR T1 - Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology JF - bioRxiv DO - 10.1101/2020.05.28.122291 SP - 2020.05.28.122291 AU - C. Allison Stewart AU - Carl M. Gay AU - Kavya Ramkumar AU - Kasey R. Cargill AU - Robert J. Cardnell AU - Monique B. Nilsson AU - Simon Heeke AU - Elizabeth M. Park AU - Samrat T. Kundu AU - Lixia Diao AU - Qi Wang AU - Li Shen AU - Yuanxin Xi AU - Bingnan Zhang AU - Carminia Maria Della Corte AU - Youhong Fan AU - Kiran Kundu AU - Boning Gao AU - Kimberley Avila AU - Curtis R. Pickering AU - Faye M. Johnson AU - Jianjun Zhang AU - Humam Kadara AU - John D. Minna AU - Don L. Gibbons AU - Jing Wang AU - John V. Heymach AU - Lauren Averett Byers Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/28/2020.05.28.122291.abstract N2 - COVID-19 is an infectious disease caused by SARS-CoV-2, which enters host cells via the cell surface proteins ACE2 and TMPRSS2. Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2. We find that ACE2 expression is restricted to a select population of highly epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium, induces metabolic and transcriptional changes consistent with epithelial to mesenchymal transition (EMT), including upregulation of ZEB1 and AXL, resulting in an increased EMT score. Additionally, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT via TGFbeta, ZEB1 overexpression and onset of EGFR TKI inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL-inhibition and ZEB1-reduction, as with bemcentinib, offers a potential strategy to reverse this effect. These observations highlight the utility of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses, and offer important insights into the potential mechanisms underlying the morbidity and mortality of COVID-19 in healthy patients and cancer patients alike.Competing Interest StatementL.A.B. serves on advisory committees for AstraZeneca, AbbVie, GenMab, BergenBio, Pharma Mar SA, Sierra Oncology, Merck, Bristol Myers Squibb, Genentech, and Pfizer and has research support from AbbVie, AstraZeneca, GenMab, Sierra Oncology, Tolero Pharmaceuticals. J.V.H. serves on advisory committees for AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, GSK, Guardant Health, Hengrui, Lilly, Novartis, Spectrum, EMD Serono, and Synta, has research support from AstraZeneca, Bayer, GlaxoSmithKline, and Spectrum and royalties and licensing fees from Spectrum. D.L.G. has served on scientific advisory committees for AstraZeneca, GlaxoSmithKline, Sanofi and Janssen and has received research support from Janssen, Takeda, Ribon Therapeutics, Astellas and AstraZeneca. C.M.G. received research funding from AstraZeneca. Otherwise, there are no pertinent financial or non-financial conflicts of interest to report. ER -