Club cells form lung adenocarcinomas and maintain the alveoli of adult mice

Abstract
Data availability
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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).

The following data sets were generated

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https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE94981

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Article and author information

Author details

Magda Spella

Department of Physiology, University of Patras, Rio, Greece

For correspondence
magsp@upatras.gr

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2505-7778
Ioannis Lilis

Department of Physiology, University of Patras, Rio, Greece

Competing interests
The authors declare that no competing interests exist.
Mario AA Pepe

Comprehensive Pneumology Center (CPC), Helmholtz Center Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Yuanyuan Chen

Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

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The authors declare that no competing interests exist.
Maria Armaka

Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece

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The authors declare that no competing interests exist.
Anne-Sophie Lamort

Comprehensive Pneumology Center (CPC), Helmholtz Center Munich, Munich, Germany

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The authors declare that no competing interests exist.
Dimitra E Zazara

Department of Physiology, University of Patras, Rio, Greece

Competing interests
The authors declare that no competing interests exist.
Fani Roumelioti

Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece

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The authors declare that no competing interests exist.
Malamati Vreka

Department of Physiology, University of Patras, Rio, Greece

Competing interests
The authors declare that no competing interests exist.
Nikolaos I Kanellakis

Department of Physiology, University of Patras, Rio, Greece

Competing interests
The authors declare that no competing interests exist.
Darcy E Wagner

Comprehensive Pneumology Center (CPC), Helmholtz Center Munich, Munich, Germany

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The authors declare that no competing interests exist.
Anastasios D Giannou

Department of Physiology, University of Patras, Rio, Greece

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The authors declare that no competing interests exist.
Vasileios Armenis

Department of Physiology, University of Patras, Rio, Greece

Competing interests
The authors declare that no competing interests exist.
Kristina AM Arendt

Comprehensive Pneumology Center (CPC), Helmholtz Center Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Laura V Klotz

Comprehensive Pneumology Center (CPC), Helmholtz Center Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Dimitrios Toumpanakis

1st Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, Athens, Greece

Competing interests
The authors declare that no competing interests exist.
Vassiliki Karavana

1st Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, Athens, Greece

Competing interests
The authors declare that no competing interests exist.
Spyros G Zakynthinos

1st Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, Athens, Greece

Competing interests
The authors declare that no competing interests exist.
Ioanna Giopanou

Department of Physiology, University of Patras, Rio, Greece

Competing interests
The authors declare that no competing interests exist.
Antonia Marazioti

Department of Physiology, University of Patras, Rio, Greece

Competing interests
The authors declare that no competing interests exist.
Vassilis Aidinis

Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece

Competing interests
The authors declare that no competing interests exist.
Rocio Sotillo

Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0855-7917
Georgios T Stathopoulos

Department of Physiology, University of Patras, Rio, Greece

For correspondence
gstathop@upatras.gr

Competing interests
The authors declare that no competing interests exist.

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.

Copyright

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.