Cell surface GRP78 promotes stemness in normal and neoplastic cells

Sci Rep. 2020 Feb 26;10(1):3474. doi: 10.1038/s41598-020-60269-y.

Abstract

Reliable approaches to identify stem cell mechanisms that mediate aggressive cancer could have great therapeutic value, based on the growing evidence of embryonic signatures in metastatic cancers. However, how to best identify and target stem-like mechanisms aberrantly acquired by cancer cells has been challenging. We harnessed the power of reprogramming to examine GRP78, a chaperone protein generally restricted to the endoplasmic reticulum in normal tissues, but which is expressed on the cell surface of human embryonic stem cells and many cancer types. We have discovered that (1) cell surface GRP78 (sGRP78) is expressed on iPSCs and is important in reprogramming, (2) sGRP78 promotes cellular functions in both pluripotent and breast cancer cells (3) overexpression of GRP78 in breast cancer cells leads to an induction of a CD24-/CD44+ tumor initiating cell (TIC) population (4) sGRP78+ breast cancer cells are enriched for stemness genes and appear to be a subset of TICs (5) sGRP78+ breast cancer cells show an enhanced ability to seed metastatic organ sites in vivo. These collective findings show that GRP78 has important functions in regulating both pluripotency and oncogenesis, and suggest that sGRP78 marks a stem-like population in breast cancer cells that has increased metastatic potential in vivo.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Differentiation*
  • Cell Line, Tumor
  • Cell Self Renewal*
  • Cell Transformation, Neoplastic
  • Cellular Reprogramming
  • Female
  • HEK293 Cells
  • Heat-Shock Proteins / antagonists & inhibitors
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Knockout
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transplantation, Heterologous

Substances

  • Heat-Shock Proteins
  • RNA, Small Interfering
  • Transcription Factors
  • molecular chaperone GRP78