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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.

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


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.


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

[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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