Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma.

TitleNkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma.
Publication TypeJournal Article
Year of Publication2013
AuthorsSnyder EL, Watanabe H, Magendantz M, Hoersch S, Chen TA, Wang DG, Crowley D, Whittaker CA, Meyerson M, Kimura S, Jacks T
JournalMol Cell
Volume50
Issue2
Pagination185-99
Date Published2013 Apr 25
ISSN1097-4164
KeywordsAdenocarcinoma, Animals, Binding Sites, Cell Differentiation, Cell Proliferation, Cell Transformation, Neoplastic, Gastric Mucosa, Gene Expression Regulation, Neoplastic, Hepatocyte Nuclear Factor 3-alpha, Hepatocyte Nuclear Factor 3-beta, Hepatocyte Nuclear Factor 4, Humans, Hyperplasia, Lung, Lung Neoplasms, Mice, Mice, Transgenic, Mutation, Missense, Nuclear Proteins, Organ Specificity, Protein Binding, Proto-Oncogene Proteins p21(ras), Pulmonary Alveoli, Respiratory Mucosa, Stomach, Thyroid Nuclear Factor 1, Transcription Factors, Transcriptional Activation, Transcriptome, Tumor Burden
Abstract

Tissue-specific differentiation programs become dysregulated during cancer evolution. The transcription factor Nkx2-1 is a master regulator of pulmonary differentiation that is downregulated in poorly differentiated lung adenocarcinoma. Here we use conditional murine genetics to determine how the identity of lung epithelial cells changes upon loss of their master cell-fate regulator. Nkx2-1 deletion in normal and neoplastic lungs causes not only loss of pulmonary identity but also conversion to a gastric lineage. Nkx2-1 is likely to maintain pulmonary identity by recruiting transcription factors Foxa1 and Foxa2 to lung-specific loci, thus preventing them from binding gastrointestinal targets. Nkx2-1-negative murine lung tumors mimic mucinous human lung adenocarcinomas, which express gastric markers. Loss of the gastrointestinal transcription factor Hnf4α leads to derepression of the embryonal proto-oncogene Hmga2 in Nkx2-1-negative tumors. These observations suggest that loss of both active and latent differentiation programs is required for tumors to reach a primitive, poorly differentiated state.

DOI10.1016/j.molcel.2013.02.018
Alternate JournalMol. Cell
PubMed ID23523371
PubMed Central IDPMC3721642
Grant ListP30 CA014051 / CA / NCI NIH HHS / United States
U01 CA084306 / CA / NCI NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
K08-CA154784-01 / CA / NCI NIH HHS / United States
R01 CA109038 / CA / NCI NIH HHS / United States
U01-CA84306 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
K08 CA154784 / CA / NCI NIH HHS / United States