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

  1. Magda Spella  Is a corresponding author
  2. Ioannis Lilis
  3. Mario AA Pepe
  4. Yuanyuan Chen
  5. Maria Armaka
  6. Anne-Sophie Lamort
  7. Dimitra E Zazara
  8. Fani Roumelioti
  9. Malamati Vreka
  10. Nikolaos I Kanellakis
  11. Darcy E Wagner
  12. Anastasios D Giannou
  13. Vasileios Armenis
  14. Kristina AM Arendt
  15. Laura V Klotz
  16. Dimitrios Toumpanakis
  17. Vassiliki Karavana
  18. Spyros G Zakynthinos
  19. Ioanna Giopanou
  20. Antonia Marazioti
  21. Vassilis Aidinis
  22. Rocio Sotillo
  23. Georgios T Stathopoulos  Is a corresponding author
  1. University of Patras, Greece
  2. Helmholtz Center Munich, Germany
  3. German Cancer Research Center (DKFZ), Germany
  4. Biomedical Sciences Research Center Alexander Fleming, Greece
  5. 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).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2505-7778
  2. Ioannis Lilis

    Department of Physiology, University of Patras, Rio, Greece
    Competing interests
    The authors declare that no competing interests exist.
  3. Mario AA Pepe

    Comprehensive Pneumology Center (CPC), Helmholtz Center Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Yuanyuan Chen

    Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Maria Armaka

    Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
    Competing interests
    The authors declare that no competing interests exist.
  6. Anne-Sophie Lamort

    Comprehensive Pneumology Center (CPC), Helmholtz Center Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Dimitra E Zazara

    Department of Physiology, University of Patras, Rio, Greece
    Competing interests
    The authors declare that no competing interests exist.
  8. Fani Roumelioti

    Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
    Competing interests
    The authors declare that no competing interests exist.
  9. Malamati Vreka

    Department of Physiology, University of Patras, Rio, Greece
    Competing interests
    The authors declare that no competing interests exist.
  10. Nikolaos I Kanellakis

    Department of Physiology, University of Patras, Rio, Greece
    Competing interests
    The authors declare that no competing interests exist.
  11. Darcy E Wagner

    Comprehensive Pneumology Center (CPC), Helmholtz Center Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Anastasios D Giannou

    Department of Physiology, University of Patras, Rio, Greece
    Competing interests
    The authors declare that no competing interests exist.
  13. Vasileios Armenis

    Department of Physiology, University of Patras, Rio, Greece
    Competing interests
    The authors declare that no competing interests exist.
  14. Kristina AM Arendt

    Comprehensive Pneumology Center (CPC), Helmholtz Center Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Laura V Klotz

    Comprehensive Pneumology Center (CPC), Helmholtz Center Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  16. 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.
  17. 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.
  18. 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.
  19. Ioanna Giopanou

    Department of Physiology, University of Patras, Rio, Greece
    Competing interests
    The authors declare that no competing interests exist.
  20. Antonia Marazioti

    Department of Physiology, University of Patras, Rio, Greece
    Competing interests
    The authors declare that no competing interests exist.
  21. Vassilis Aidinis

    Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
    Competing interests
    The authors declare that no competing interests exist.
  22. Rocio Sotillo

    Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0855-7917
  23. 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.

Reviewing Editor

  1. Jody Rosenblatt, King's College London, United Kingdom

Publication history

  1. Received: January 28, 2019
  2. Accepted: May 24, 2019
  3. Accepted Manuscript published: May 29, 2019 (version 1)
  4. 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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  1. Magda Spella
  2. Ioannis Lilis
  3. Mario AA Pepe
  4. Yuanyuan Chen
  5. Maria Armaka
  6. Anne-Sophie Lamort
  7. Dimitra E Zazara
  8. Fani Roumelioti
  9. Malamati Vreka
  10. Nikolaos I Kanellakis
  11. Darcy E Wagner
  12. Anastasios D Giannou
  13. Vasileios Armenis
  14. Kristina AM Arendt
  15. Laura V Klotz
  16. Dimitrios Toumpanakis
  17. Vassiliki Karavana
  18. Spyros G Zakynthinos
  19. Ioanna Giopanou
  20. Antonia Marazioti
  21. Vassilis Aidinis
  22. Rocio Sotillo
  23. Georgios T Stathopoulos
(2019)
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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