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Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2–Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology
INTRODUCTION: Coronavirus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which enters host cells through the cell surface proteins ACE2 and TMPRSS2. METHODS: Using a variety of normal and malignant models and tissues from the aerodigesti...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
International Association for the Study of Lung Cancer. Published by Elsevier Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282443/ https://www.ncbi.nlm.nih.gov/pubmed/34274504 http://dx.doi.org/10.1016/j.jtho.2021.07.002 |
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author | Stewart, C. Allison Gay, Carl M. Ramkumar, Kavya Cargill, Kasey R. Cardnell, Robert J. Nilsson, Monique B. Heeke, Simon Park, Elizabeth M. Kundu, Samrat T. Diao, Lixia Wang, Qi Shen, Li Xi, Yuanxin Zhang, Bingnan Della Corte, Carminia Maria Fan, Youhong Kundu, Kiran Gao, Boning Avila, Kimberley Pickering, Curtis R. Johnson, Faye M. Zhang, Jianjun Kadara, Humam Minna, John D. Gibbons, Don L. Wang, Jing Heymach, John V. Byers, Lauren Averett |
author_facet | Stewart, C. Allison Gay, Carl M. Ramkumar, Kavya Cargill, Kasey R. Cardnell, Robert J. Nilsson, Monique B. Heeke, Simon Park, Elizabeth M. Kundu, Samrat T. Diao, Lixia Wang, Qi Shen, Li Xi, Yuanxin Zhang, Bingnan Della Corte, Carminia Maria Fan, Youhong Kundu, Kiran Gao, Boning Avila, Kimberley Pickering, Curtis R. Johnson, Faye M. Zhang, Jianjun Kadara, Humam Minna, John D. Gibbons, Don L. Wang, Jing Heymach, John V. Byers, Lauren Averett |
author_sort | Stewart, C. Allison |
collection | PubMed |
description | INTRODUCTION: Coronavirus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which enters host cells through the cell surface proteins ACE2 and TMPRSS2. METHODS: 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. RESULTS: We find that ACE2 expression is restricted to a select population of 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 up-regulation of ZEB1 and AXL, resulting in an increased EMT score. In addition, 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 through the transforming growth factor-β, ZEB1 overexpression, and onset of EGFR tyrosine kinase 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, offer a potential strategy to reverse this effect. CONCLUSIONS: These observations highlight the use 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 coronavirus disease 2019 in healthy patients and patients with cancer alike. |
format | Online Article Text |
id | pubmed-8282443 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | International Association for the Study of Lung Cancer. Published by Elsevier Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82824432021-07-20 Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2–Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology Stewart, C. Allison Gay, Carl M. Ramkumar, Kavya Cargill, Kasey R. Cardnell, Robert J. Nilsson, Monique B. Heeke, Simon Park, Elizabeth M. Kundu, Samrat T. Diao, Lixia Wang, Qi Shen, Li Xi, Yuanxin Zhang, Bingnan Della Corte, Carminia Maria Fan, Youhong Kundu, Kiran Gao, Boning Avila, Kimberley Pickering, Curtis R. Johnson, Faye M. Zhang, Jianjun Kadara, Humam Minna, John D. Gibbons, Don L. Wang, Jing Heymach, John V. Byers, Lauren Averett J Thorac Oncol Original Article INTRODUCTION: Coronavirus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which enters host cells through the cell surface proteins ACE2 and TMPRSS2. METHODS: 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. RESULTS: We find that ACE2 expression is restricted to a select population of 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 up-regulation of ZEB1 and AXL, resulting in an increased EMT score. In addition, 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 through the transforming growth factor-β, ZEB1 overexpression, and onset of EGFR tyrosine kinase 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, offer a potential strategy to reverse this effect. CONCLUSIONS: These observations highlight the use 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 coronavirus disease 2019 in healthy patients and patients with cancer alike. International Association for the Study of Lung Cancer. Published by Elsevier Inc. 2021-11 2021-07-16 /pmc/articles/PMC8282443/ /pubmed/34274504 http://dx.doi.org/10.1016/j.jtho.2021.07.002 Text en © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Original Article Stewart, C. Allison Gay, Carl M. Ramkumar, Kavya Cargill, Kasey R. Cardnell, Robert J. Nilsson, Monique B. Heeke, Simon Park, Elizabeth M. Kundu, Samrat T. Diao, Lixia Wang, Qi Shen, Li Xi, Yuanxin Zhang, Bingnan Della Corte, Carminia Maria Fan, Youhong Kundu, Kiran Gao, Boning Avila, Kimberley Pickering, Curtis R. Johnson, Faye M. Zhang, Jianjun Kadara, Humam Minna, John D. Gibbons, Don L. Wang, Jing Heymach, John V. Byers, Lauren Averett Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2–Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology |
title | Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2–Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology |
title_full | Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2–Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology |
title_fullStr | Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2–Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology |
title_full_unstemmed | Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2–Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology |
title_short | Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2–Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology |
title_sort | lung cancer models reveal severe acute respiratory syndrome coronavirus 2–induced epithelial-to-mesenchymal transition contributes to coronavirus disease 2019 pathophysiology |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282443/ https://www.ncbi.nlm.nih.gov/pubmed/34274504 http://dx.doi.org/10.1016/j.jtho.2021.07.002 |
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