FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer
- University of Utah, United States
- University of Pennsylvania, United States
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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FoxA1 and FoxA2 are required for gastric differentiation in NKX2-1-negative lung adenocarcinomaNCBI Gene Expression Omnibus, GSE115901.
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KRAS mutant lung adenocarcinomaCancer Discovery, 10.1158/2159-8290.
Article and author information
Author details
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.
Reviewing Editor
- Richard M White, Memorial Sloan Kettering Cancer Center, United States
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.
Version history
- Received: June 15, 2018
- Accepted: November 24, 2018
- Accepted Manuscript published: November 26, 2018 (version 1)
- 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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FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer
eLife 7:e38579.
https://doi.org/10.7554/eLife.38579
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