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

Mol Cell. 2013 Apr 25;50(2):185-99. doi: 10.1016/j.molcel.2013.02.018. Epub 2013 Mar 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Animals
  • Binding Sites
  • Cell Differentiation*
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Gastric Mucosa / metabolism
  • Gene Expression Regulation, Neoplastic
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Humans
  • Hyperplasia / metabolism
  • Lung / metabolism
  • Lung / pathology
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Transgenic
  • Mutation, Missense
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / physiology
  • Organ Specificity
  • Protein Binding
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Pulmonary Alveoli / metabolism
  • Pulmonary Alveoli / pathology
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Stomach / pathology
  • Thyroid Nuclear Factor 1
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology
  • Transcriptional Activation
  • Transcriptome
  • Tumor Burden

Substances

  • Foxa1 protein, mouse
  • Foxa2 protein, mouse
  • Hepatocyte Nuclear Factor 3-alpha
  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • Nkx2-1 protein, mouse
  • Nuclear Proteins
  • Thyroid Nuclear Factor 1
  • Transcription Factors
  • Hepatocyte Nuclear Factor 3-beta
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)

Associated data

  • GEO/GSE36473
  • GEO/GSE43252