An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma
- Huntsman Cancer Institute, University of Utah, United States
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).
Article and author information
Author details
Michelle C Mendoza
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
- Maureen E Murphy, The Wistar Institute, United States
Version history
- Received: January 22, 2021
- Accepted: April 5, 2021
- Accepted Manuscript published: April 6, 2021 (version 1)
- Version of Record published: May 6, 2021 (version 2)
- 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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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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