Title | Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Snyder EL, Watanabe H, Magendantz M, Hoersch S, Chen TA, Wang DG, Crowley D, Whittaker CA, Meyerson M, Kimura S, Jacks T |
Journal | Mol Cell |
Volume | 50 |
Issue | 2 |
Pagination | 185-99 |
Date Published | 2013 Apr 25 |
ISSN | 1097-4164 |
Keywords | Adenocarcinoma, 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. |
DOI | 10.1016/j.molcel.2013.02.018 |
Alternate Journal | Mol. Cell |
PubMed ID | 23523371 |
PubMed Central ID | PMC3721642 |
Grant List | P30 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 |
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