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Elife. 2018 Nov 26;7. pii: e38579. doi: 10.7554/eLife.38579.

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

Author information

1
Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, United States.
2
Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States.
3
Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, United States.
#
Contributed equally

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.

KEYWORDS:

FoxA1; FoxA2; NKX2-1; cancer biology; human; lineage switching; lung cancer; mouse

PMID:
30475207
PMCID:
PMC6303105
DOI:
10.7554/eLife.38579
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

SC, SP, TM, AJ, VB, GO, MS, LS, CS, KK, ES No competing interests declared

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