Context-Dependent Impact of RAS Oncogene Expression on Cellular Reprogramming to Pluripotency

Stem Cell Reports. 2019 May 14;12(5):1099-1112. doi: 10.1016/j.stemcr.2019.04.006. Epub 2019 May 2.

Abstract

Induction of pluripotency in somatic cells with defined genetic factors has been successfully used to investigate the mechanisms of disease initiation and progression. Cellular reprogramming and oncogenic transformation share common features; both involve undergoing a dramatic change in cell identity, and immortalization is a key step for cancer progression that enhances reprogramming. However, there are very few examples of complete successful reprogramming of tumor cells. Here we address the effect of expressing an active oncogene, RAS, on the process of reprogramming and found that, while combined expression with reprogramming factors enhanced dedifferentiation, expression within the context of neoplastic transformation impaired reprogramming. RAS induces expression changes that promote loss of cell identity and acquisition of stemness in a paracrine manner and these changes result in reprogramming when combined with reprogramming factors. When cells carry cooperating oncogenic defects, RAS drives cells into an incompatible cellular fate of malignancy.

Keywords: Ras; cell plasticity; cell reprogramming; iPSC; oncogenes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Dedifferentiation / genetics*
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • Cellular Reprogramming / genetics*
  • Embryo, Mammalian / cytology*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Gene Expression Regulation
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Mice, Transgenic
  • ras Proteins / genetics*
  • ras Proteins / metabolism

Substances

  • ras Proteins