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FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer

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Cite this article as: eLife 2018;7:e38579 doi: 10.7554/eLife.38579

Abstract

Changes in cancer cell identity can alter malignant potential and therapeutic response. Loss of the pulmonary lineage specifier NKX2-1 augments the growth of KRAS-driven lung adenocarcinoma and causes pulmonary to gastric transdifferentiation. Here we show that the transcription factors FoxA1 and FoxA2 are required for initiation of mucinous NKX2-1-negative lung adenocarcinomas in the mouse and for activation of their gastric differentiation program. Foxa1/2 deletion severely impairs tumor initiation and causes a proximal shift in cellular identity, yielding tumors expressing markers of the squamocolumnar junction of the gastrointestinal tract. In contrast, we observe downregulation of FoxA1/2 expression in the squamous component of both murine and human lung adenosquamous carcinoma. Using sequential in vivo recombination, we find that FoxA1/2 loss in established KRAS-driven neoplasia originating from SPC-positive alveolar cells induces keratinizing squamous cell carcinomas. Thus, NKX2-1, FoxA1 and FoxA2 coordinately regulate the growth and identity of lung cancer in a context-specific manner.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Sequencing data will be deposited in GEO under accession codes GSE115901.

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The following previously published data sets were used

Article and author information

Author details

  1. Soledad A Camolotto

    Department of Pathology, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Shrivatsav Pattabiraman

    Department of Pathology, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Timothy L Mosbruger

    Bioinformatics Shared Resource, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alex Jones

    Department of Pathology, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Veronika K Belova

    Department of Pathology, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Grace Orstad

    Department of Pathology, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Mitchell Streiff

    Department of Pathology, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Lydia Salmond

    Department of Pathology, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Chris Stubben

    Bioinformatics Shared Resource, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Klaus H Kaestner

    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1228-021X
  11. Eric Snyder

    Department of Pathology, University of Utah, Salt Lake City, United States
    For correspondence
    eric.snyder@hci.utah.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3591-3195

Funding

National Cancer Institute (R01212415)

  • Eric Snyder

Burroughs Wellcome Fund (Career Award for Medical Scientists)

  • Eric Snyder

V Foundation for Cancer Research (Scholar Award)

  • Eric Snyder

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#15-07009) of the University of Utah.

Reviewing Editor

  1. Richard M White, Memorial Sloan Kettering Cancer Center, United States

Publication history

  1. Received: May 22, 2018
  2. Accepted: November 24, 2018
  3. Accepted Manuscript published: November 26, 2018 (version 1)
  4. Version of Record published: December 21, 2018 (version 2)

Copyright

© 2018, Camolotto 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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