Asymmetric cell division promotes therapeutic resistance in glioblastoma stem cells

JCI Insight. 2021 Feb 8;6(3):e130510. doi: 10.1172/jci.insight.130510.

Abstract

Asymmetric cell division (ACD) enables the maintenance of a stem cell population while simultaneously generating differentiated progeny. Cancer stem cells (CSCs) undergo multiple modes of cell division during tumor expansion and in response to therapy, yet the functional consequences of these division modes remain to be determined. Using a fluorescent reporter for cell surface receptor distribution during mitosis, we found that ACD generated a daughter cell with enhanced therapeutic resistance and increased coenrichment of EGFR and neurotrophin receptor (p75NTR) from a glioblastoma CSC. Stimulation of both receptors antagonized differentiation induction and promoted self-renewal capacity. p75NTR knockdown enhanced the therapeutic efficacy of EGFR inhibition, indicating that coinheritance of p75NTR and EGFR promotes resistance to EGFR inhibition through a redundant mechanism. These data demonstrate that ACD produces progeny with coenriched growth factor receptors, which contributes to the generation of a more therapeutically resistant CSC population.

Keywords: Brain cancer; Cancer; Cell Biology; Stem cells.

Publication types

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

MeSH terms

  • AC133 Antigen / metabolism
  • Asymmetric Cell Division*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Self Renewal
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Gene Knockdown Techniques
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • Humans
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Receptors, Nerve Growth Factor / antagonists & inhibitors
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / metabolism

Substances

  • AC133 Antigen
  • NGFR protein, human
  • Nerve Tissue Proteins
  • PROM1 protein, human
  • Receptors, Nerve Growth Factor
  • EGFR protein, human
  • ErbB Receptors