TY - JOUR
T1 - Asymmetric cell division promotes therapeutic resistance in glioblastoma stem cells
AU - Hitomi, Masahiro
AU - Chumakova, Anastasia P
AU - Silver, Daniel J
AU - Knudsen, Arnon M
AU - Pontius, W Dean
AU - Murphy, Stephanie
AU - Anand, Neha
AU - Kristensen, Bjarne W
AU - Lathia, Justin D
PY - 2021/2/8
Y1 - 2021/2/8
N2 - 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.
AB - 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.
KW - AC133 Antigen/metabolism
KW - Asymmetric Cell Division
KW - Brain Neoplasms/drug therapy
KW - Cell Differentiation
KW - Cell Line, Tumor
KW - Cell Self Renewal
KW - Drug Resistance, Neoplasm
KW - ErbB Receptors/antagonists & inhibitors
KW - Gene Knockdown Techniques
KW - Glioblastoma/drug therapy
KW - Humans
KW - Neoplastic Stem Cells/drug effects
KW - Nerve Tissue Proteins/antagonists & inhibitors
KW - Receptors, Nerve Growth Factor/antagonists & inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85102091030&partnerID=8YFLogxK
U2 - 10.1172/JCI.INSIGHT.130510
DO - 10.1172/JCI.INSIGHT.130510
M3 - Journal article
C2 - 33351787
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 3
M1 - e130510
ER -