Your browser doesn't support javascript.
SARS-CoV-2 infection induces EMT-like molecular changes, including ZEB1-mediated repression of the viral receptor ACE2, in lung cancer models
Annals of Oncology ; 31:S1015, 2020.
Article in English | EMBASE | ID: covidwho-806229
ABSTRACT

Background:

SARS-CoV-2 infection is the cause of the respiratory illness COVID-19, which presents most frequently with respiratory symptoms. SARS-CoV-2 cell entry requires interactions with ACE2 and TMPRSS2 on the surface of the host cell. Cancer patients and, specifically, those with thoracic malignancies seem to experience poorer clinical outcomes.

Methods:

We utilized bulk and single-cell transcriptional data from a combination of normal and malignant tissues and cells from aerodigestive and respiratory tracts to explore mechanisms governing the expression of ACE2 and TMPRSS2. Additionally, we determined the effect of EMT induction, ZEB1 modulation, and SARS-CoV-2 infection on ACE2 expression.

Results:

Our bulk data suggests that aerodigestive and lung cancer models express a broad range of ACE2 and TMRPSS2, particularly in epithelial cells, and would serve as good models for studying SARS-CoV-2 infection. We assessed the relationship between ACE2 and epithelial differentiation in numerous datasets, and found consistent positive correlations with transcriptional and microRNA signifiers of epithelial differentiation. The miR-200 familyzinc finger E-box-binding homeobox 1 (ZEB1) pathway, which is an established regulator of EMT, also directly regulates ACE2 expression, likely via putative ZEB1 repressor sites located in the ACE2 promoter. Furthermore, SARS-CoV-2 infection reduces ACE2 expression and shifts cells to a more mesenchymal phenotype with loss of EPCAM and upregulation of ZEB1 and other EMT-associated genes.

Conclusions:

ACE2-positive cells are almost exclusively epithelial and unexpectedly rare, considering the devastating impact of this infection. Following viral entry, SARS-CoV-2 infection induces molecular changes within the cells that are reminiscent of EMT, including increased ZEB1. ZEB1, in turn, appears to directly repress the expression of ACE2. This SARS-CoV-2-induced ACE2 deficiency, compounded by the downregulation of genes, including claudins, which play a critical role in restricting epithelial and endothelial permeability, exposes respiratory cells to increased risk of edema and acute respiratory distress syndrome (ARDS). Legal entity responsible for the study The authors.

Funding:

NIH/NCI R01-CA207295 (L.A.B.), NIH/NCI U01-CA213273 (L.A.B., J.V.H.), CCSG P30-CA01667 (L.A.B.), University of Texas SPORE in Lung Cancer P5-CA070907 (L.A.B., D.L.G., J.V.H., C.M.G.), the Department of Defense (LC170171;L.A.B.), Khalifa Bin Zayed Al Nahyan Foundation (C.M.G.), RP170067 (EMP), through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program and Andrew Sabin Family Fellowship, and The Rexanna Foundation for Fighting Lung Cancer. Disclosure C. Gay Research grant/Funding (self) Astra Zeneca. J.V. Heymach Advisory/Consultancy AstraZeneca;Advisory/Consultancy Boehringer Ingelheim;Advisory/Consultancy Exelixis;Advisory/Consultancy Genentech;Advisory/Consultancy GlaxoSmithKline;Advisory/Consultancy Guardant Health;Advisory/Consultancy Hengrui;Advisory/Consultancy Spectrum. L.A. Byers Advisory/Consultancy, Research grant/Funding (self) AstraZeneca;Advisory/Consultancy, Research grant/Funding (self) AbbVie;Advisory/Consultancy, Research grant/Funding (self) GenMab;Advisory/Consultancy BergenBio;Advisory/Consultancy Pharma Mar SA;Advisory/Consultancy, Research grant/Funding (self) Sierra Oncology;Advisory/Consultancy Merck;Advisory/Consultancy Bristol Myers Squibb;Advisory/Consultancy Genentech;Advisory/Consultancy Pfizer;Research grant/Funding (self) Tolero Pharmaceuticals. All other authors have declared no conflicts of interest.

Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Annals of Oncology Year: 2020 Document Type: Article

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Annals of Oncology Year: 2020 Document Type: Article