An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma

Abstract

Cancer cells undergo lineage switching during natural progression and in response to therapy. NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation and harbors a distinct spectrum of driver oncogenes. In murine BRAFV600E driven lung adenocarcinoma, NKX2-1 is required for early tumorigenesis, but dispensable for established tumor growth. NKX2-1-deficient, BRAFV600E driven tumors resemble human IMA and exhibit a distinct response to BRAF/MEK inhibitors. Whereas BRAF/MEK inhibitors drive NKX2-1-positive tumor cells into quiescence, NKX2-1-negative cells fail to exit the cell cycle after the same therapy. BRAF/MEK inhibitors induce cell identity switching in NKX2-1-negative lung tumors within the gastric lineage, which is driven in part by WNT signaling and FoxA1/2. These data elucidate a complex, reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of lung adenocarcinoma identity that is likely to impact lineage-specific therapeutic strategies.

Data availability

All sequencing data generated in this study are available at Gene Expression Omnibus (GEO: GSE145152).

The following data sets were generated

Article and author information

Author details

  1. Rediet Zewdu

    Department of Pathology, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Elnaz Mirzaei Mehrabad

    School of Computing, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kelley Ingram

    Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Pengshu Fang

    Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Katherine L Gillis

    Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Soledad A Camolotto

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

    Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Alex Jones

    Department of Pathology, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Michelle C Mendoza

    Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6490-1794
  10. Benjamin T Spike

    Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Eric L Snyder

    Department of Pathology and Department of Oncological Sciences, Huntsman Cancer Institute, 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

V Foundation for Cancer Research (V Scholar Award)

  • Eric L Snyder

Burroughs Wellcome Fund (Career Award for Medical Scientists)

  • Eric L Snyder

National Cancer Institute (R01CA212415)

  • Eric L Snyder

National Cancer Institute (R01CA240317)

  • Eric L Snyder

National Cancer Institute (F31CA243427)

  • Grace Orstad

Lung Cancer Center, Huntsman Cancer Institute (Pilot Project Award)

  • Benjamin T Spike
  • Eric L 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: All animal work was done in accordance with a protocol (#18-08005) approved by the University of Utah Institutional Animal Care and Use Committee.

Reviewing Editor

  1. Maureen E Murphy, The Wistar Institute, United States

Publication history

  1. Received: January 22, 2021
  2. Accepted: April 5, 2021
  3. Accepted Manuscript published: April 6, 2021 (version 1)
  4. Version of Record published: May 6, 2021 (version 2)
  5. Version of Record updated: August 20, 2021 (version 3)

Copyright

© 2021, Zewdu 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. Rediet Zewdu
  2. Elnaz Mirzaei Mehrabad
  3. Kelley Ingram
  4. Pengshu Fang
  5. Katherine L Gillis
  6. Soledad A Camolotto
  7. Grace Orstad
  8. Alex Jones
  9. Michelle C Mendoza
  10. Benjamin T Spike
  11. Eric L Snyder
(2021)
An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma
eLife 10:e66788.
https://doi.org/10.7554/eLife.66788

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