Heterogeneity and dynamics of active Kras-induced dysplastic lineages from mouse corpus stomach

Nat Commun. 2019 Dec 5;10(1):5549. doi: 10.1038/s41467-019-13479-6.

Abstract

Dysplasia is considered a key transition state between pre-cancer and cancer in gastric carcinogenesis. However, the cellular or phenotypic heterogeneity and mechanisms of dysplasia progression have not been elucidated. We have established metaplastic and dysplastic organoid lines, derived from Mist1-Kras(G12D) mouse stomach corpus and studied distinct cellular behaviors and characteristics of metaplastic and dysplastic organoids. We also examined functional roles for Kras activation in dysplasia progression using Selumetinib, a MEK inhibitor, which is a downstream mediator of Kras signaling. Here, we report that dysplastic organoids die or show altered cellular behaviors and diminished aggressive behavior in response to MEK inhibition. However, the organoids surviving after MEK inhibition maintain cellular heterogeneity. Two dysplastic stem cell (DSC) populations are also identified in dysplastic cells, which exhibited different clonogenic potentials. Therefore, Kras activation controls cellular dynamics and progression to dysplasia, and DSCs might contribute to cellular heterogeneity in dysplastic cell lineages.

Publication types

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

MeSH terms

  • Animals
  • Benzimidazoles / pharmacology
  • Cell Lineage / drug effects
  • Cell Lineage / genetics*
  • Cell Proliferation / genetics
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Gastric Mucosa / metabolism*
  • Gastric Mucosa / pathology
  • Gene Expression Regulation, Neoplastic
  • Genetic Heterogeneity / drug effects
  • Humans
  • Kinetics
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Stomach / pathology
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism

Substances

  • AZD 6244
  • Benzimidazoles
  • KRAS protein, human
  • Proto-Oncogene Proteins p21(ras)