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Asymmetric cell division promotes therapeutic resistance in glioblastoma stem cells

Research output: Contribution to journalJournal articlepeer-review

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  • Masahiro Hitomi
  • Anastasia P Chumakova
  • Daniel J Silver
  • Arnon M Knudsen
  • W Dean Pontius
  • Stephanie Murphy
  • Neha Anand
  • Bjarne W Kristensen
  • Justin D Lathia
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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.

Original languageEnglish
Article numbere130510
JournalJCI Insight
Volume6
Issue number3
ISSN2379-3708
DOIs
Publication statusPublished - 8 Feb 2021

    Research areas

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

ID: 71934730