title: Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma.
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.
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Snyder
authors.forename: Hideo
authors.initials: H
authors.lastname: Watanabe
authors.forename: Margaret
authors.initials: M
authors.lastname: Magendantz
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hoersch
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Chen
authors.forename: Diana G
authors.initials: DG
authors.lastname: Wang
authors.forename: Denise
authors.initials: D
authors.lastname: Crowley
authors.forename: Charles A
authors.initials: CA
authors.lastname: Whittaker
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Shioko
authors.initials: S
authors.lastname: Kimura
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009928:Organ Specificity; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D013270:Stomach / Q000473:pathology; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation; D059467:Transcriptome; D047368:Tumor Burden
chemical_list: C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; C000715470:MAS1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)