Club cells form lung adenocarcinomas and maintain the alveoli of adult mice
- University of Patras, Greece
- Helmholtz Center Munich, Germany
- German Cancer Research Center (DKFZ), Germany
- Biomedical Sciences Research Center Alexander Fleming, Greece
- Evangelismos Hospital, Greece
Abstract
Lung cancer and chronic lung diseases impose major disease burdens worldwide and are caused by inhaled noxious agents including tobacco smoke. The cellular origins of environmental-induced lung tumors and of the dysfunctional airway and alveolar epithelial turnover observed with chronic lung diseases are unknown. To address this, we combined mouse models of genetic labeling and ablation of airway (club) and alveolar cells with exposure to environmental noxious and carcinogenic agents. Club cells are shown to survive KRAS mutations and to form lung tumors after tobacco carcinogen exposure. Increasing numbers of club cells are found in the alveoli with aging and after lung injury, but go undetected since they express alveolar proteins. Ablation of club cells prevents chemical lung tumors and causes alveolar destruction in adult mice. Hence club cells are important in alveolar maintenance and carcinogenesis and may be a therapeutic target against premalignancy and chronic lung disease.
Data availability
All raw data produced in this study are provided as *.xlsx source data Supplements. The microarray data produced by this study were deposited at GEO (http://www.ncbi.nlm.nih.gov/geo/; Accession ID: GSE94981). Previously reported [36-40] murine ATII and human AEC, ATII, AMΦ, non-smokers lung, and LUAD microarray data are available at GEO using Accession IDs GSE82154, GSE55459, GSE46749, GSE18816, and GSE43458).
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Epithelial signatures of chemical-induced lung adenocarcinomaGene Expression Omnibus GSE94981.
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Plasticity of airway epithelial cell transcriptome in response to flagellin.NCBI Gene Expression Omnibus, GSE55459.
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Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS).NCBI Gene Expression Omnibus, GSE46749.
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ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer.NCBI Gene Expression Omnibus, GSE43458.
Article and author information
Author details
Funding
H2020 European Research Council (260524)
- Georgios T Stathopoulos
Hellenic State Scholarship Foundation (Post-doctoral Research Fellowship)
- Magda Spella
Howard Hughes Medical Institute (International Research Scholars Award)
- Rocio Sotillo
German Center for Lung Research
- Kristina AM Arendt
- Laura V Klotz
- Georgios T Stathopoulos
Hellenic Thoracic Society (PhD Fellowship)
- Malamati Vreka
- Anastasios D Giannou
H2020 European Research Council (281614)
- Rocio Sotillo
H2020 European Research Council (679345)
- Georgios T Stathopoulos
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Experiments were designed and approved a priori by the Veterinary Administration of the Prefecture of Western Greece (approval numbers 3741/16.11.2010, 60291/3035/19.03.2012, and 118018/578/30.04.2014) and were conducted according to Directive 2010/63/EU (http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1486710385917&uri=CELEX:32010L0063).
Human subjects: Archival tissue samples of patients with lung adenocarcinoma were used in this study. The observational protocol for the original studies adhered to the Helsinki Declaration and was approved by the Ethics Committee of the University Hospital of Patras, and all patients gave written informed consent.
Reviewing Editor
- Jody Rosenblatt, King's College London, United Kingdom
Publication history
- Received: January 28, 2019
- Accepted: May 24, 2019
- Accepted Manuscript published: May 29, 2019 (version 1)
- Version of Record published: July 2, 2019 (version 2)
Copyright
© 2019, Spella et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Club cells form lung adenocarcinomas and maintain the alveoli of adult mice
eLife 8:e45571.
https://doi.org/10.7554/eLife.45571
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