Gain-of-function p53 protein transferred via small extracellular vesicles promotes conversion of fibroblasts to a cancer-associated phenotype

Cell Rep. 2021 Feb 9;34(6):108726. doi: 10.1016/j.celrep.2021.108726.

Abstract

Tumor and stromal interactions consist of reciprocal signaling through cytokines, growth factors, direct cell-cell interactions, and extracellular vesicles (EVs). Small EVs (≤200 nm) have been considered critical messengers of cellular communication during tumor development. Here, we demonstrate that gain-of-function (GOF) p53 protein can be packaged into small EVs and transferred to fibroblasts. GOF p53 protein is selectively bound by heat shock protein 90 (HSP90), a chaperone protein, and packaged into small EVs. Inhibition of HSP90 activity blocks packaging of GOF, but not wild-type, p53 in small EVs. GOF p53-containing small EVs result in their conversion to cancer-associated fibroblasts. In vivo studies reveal that GOF p53-containing small EVs can enhance tumor growth and promote fibroblast transformation into a cancer-associated phenotype. These findings provide a better understanding of the complex interactions between cancer and stromal cells and may have therapeutic implications.

Keywords: CAFs; HSP90; Nrf2; p53; small EVs.

Publication types

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

MeSH terms

  • Animals
  • Cancer-Associated Fibroblasts / metabolism*
  • Colorectal Neoplasms / metabolism
  • Extracellular Vesicles* / genetics
  • Extracellular Vesicles* / metabolism
  • Extracellular Vesicles* / transplantation
  • Female
  • Gain of Function Mutation*
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53