Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity

Dev Cell. 2022 Feb 7;57(3):310-328.e9. doi: 10.1016/j.devcel.2022.01.006.


Oncogenic Kras induces a hyper-proliferative state that permits cells to progress to neoplasms in diverse epithelial tissues. Depending on the cell of origin, this also involves lineage transformation. Although a multitude of downstream factors have been implicated in these processes, the precise chronology of molecular events controlling them remains elusive. Using mouse models, primary human tissues, and cell lines, we show that, in Kras-mutant alveolar type II cells (AEC2), FOSL1-based AP-1 factor guides the mSWI/SNF complex to increase chromatin accessibility at genomic loci controlling the expression of genes necessary for neoplastic transformation. We identified two orthogonal processes in Kras-mutant distal airway club cells. The first promoted their transdifferentiation into an AEC2-like state through NKX2.1, and the second controlled oncogenic transformation through the AP-1 complex. Our results suggest that neoplasms retain an epigenetic memory of their cell of origin through cell-type-specific transcription factors. Our analysis showed that a cross-tissue-conserved AP-1-dependent chromatin remodeling program regulates carcinogenesis.

Keywords: ATAC-seq; Fosl1; KRAS; NSCLC; adenocarcinoma; alveolar type II cell; club cell; epigenetics; intestinal stem cell; lung.

Publication types

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

MeSH terms

  • Alveolar Epithelial Cells / metabolism
  • Animals
  • Base Sequence
  • Cell Line
  • Cell Plasticity / genetics*
  • Cell Proliferation / genetics
  • Epigenesis, Genetic*
  • Epigenome
  • Epithelial Cells / cytology*
  • Epithelial Cells / metabolism*
  • Humans
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutant Proteins / metabolism
  • Mutation / genetics
  • Neoplasms / pathology
  • Nucleosomes / metabolism
  • Oncogenes*
  • Organ Specificity
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Transcription Factor AP-1 / metabolism


  • KRAS protein, human
  • Mutant Proteins
  • Nucleosomes
  • Proto-Oncogene Proteins c-fos
  • Transcription Factor AP-1
  • fos-related antigen 1
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)