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 has yet to be determined. Using a fluorescence-based system that reports the mitotic distribution of lipid rafts enriched in cell surface receptors, we found that ACD in glioblastoma CSCs generated a daughter cell with enhanced resistance to radiation and temozolomide. Single-cell analyses using our reporter system revealed that ACD also increased the co-inheritance of epidermal growth factor receptor (EGFR) and neurotrophin receptor (p75NTR), which was validated across four additional glioblastoma CSC models. Stimulation of both receptors maintained self-renewal under differentiation conditions, and stimulation with p75NTR ligands rescued the reduction in STAT3, AKT, and ERK induced by erlotinib-mediated EGFR inhibition. Finally, knockdown of p75NTR enhanced the therapeutic efficacy of EGFR inhibition in vivo. Taken together, our data indicate that co-inheritance of p75NTR and EGFR promotes resistance to EGFR inhibition through a redundant mechanism. Overall, these findings demonstrate that ACD produces progeny with enhanced growth factor receptors, which contributes to the generation of a more therapeutically resistant CSC population, and suggest that ACD needs to be considered in the development of next-generation targeting strategies.