Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2-Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology
Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved..
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.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer - 16(2021), 11 vom: 01. Nov., Seite 1821-1839 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Stewart, C Allison [VerfasserIn] |
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| Links: |
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| Themen: |
ACE2 |
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| Anmerkungen: |
Date Completed 03.11.2021 Date Revised 14.02.2024 published: Print-Electronic UpdateOf: bioRxiv. 2021 Jan 28;:. - PMID 32577652 Citation Status MEDLINE |
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| doi: |
10.1016/j.jtho.2021.07.002 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM328198773 |
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| 100 | 1 | |a Stewart, C Allison |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2-Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology |
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| 500 | |a Date Completed 03.11.2021 | ||
| 500 | |a Date Revised 14.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: bioRxiv. 2021 Jan 28;:. - PMID 32577652 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Cargill, Kasey R |e verfasserin |4 aut | |
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| 700 | 1 | |a Heeke, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Elizabeth M |e verfasserin |4 aut | |
| 700 | 1 | |a Kundu, Samrat T |e verfasserin |4 aut | |
| 700 | 1 | |a Diao, Lixia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Xi, Yuanxin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Bingnan |e verfasserin |4 aut | |
| 700 | 1 | |a Della Corte, Carminia Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Youhong |e verfasserin |4 aut | |
| 700 | 1 | |a Kundu, Kiran |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Boning |e verfasserin |4 aut | |
| 700 | 1 | |a Avila, Kimberley |e verfasserin |4 aut | |
| 700 | 1 | |a Pickering, Curtis R |e verfasserin |4 aut | |
| 700 | 1 | |a Johnson, Faye M |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jianjun |e verfasserin |4 aut | |
| 700 | 1 | |a Kadara, Humam |e verfasserin |4 aut | |
| 700 | 1 | |a Minna, John D |e verfasserin |4 aut | |
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