Asymmetric cell division promotes therapeutic resistance in glioblastoma stem cells

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.

Three-dimensional organoid culture unveils resistance to clinical therapies in adult and pediatric glioblastoma

“…More “stem-like” GBM cells are known to have greater resistance to therapy [ 2 , 9 , 15 , 21 , 47 ]. To see whether the apoptotic cells were enriched or depleted for CSCs, we treated pGBM001 organoids with the above drugs for 6 days and double immunostained for SOX2 and CC-3.…”

Inhibiting adenine synthesis attenuates glioblastoma cell stemness and temozolomide resistance

“…Findings from this study advance our understanding of these critical aspects of GBMs in several ways. First, recent work has identified numerous epigenetic and metabolic factors as essential for promoting GBM stemness and consequently as worthwhile therapeutic targets [8][9][10][11][21][22][23]. In particular, it has been shown that the guanine synthesis arm of purine metabolism can be targeted for overcoming GBM stemness [24].…”

Tumour Microenvironment Stress Promotes the Development of Drug Resistance

“…However, a newer model suggests that CSCs are not necessarily rare or quiescent and that they can also arise by dedifferentiation and reprogramming of non-CSCs [206]. Similar to normal stem cells, CSCs may undergo symmetric-cell division to self-propagate; asymmetric-cell division to produce more differentiated progeny and self-renew; or they may become quiescent, depending on the stimuli the cell receive [208][209][210][211]. However, within the context of dysregulated signalling and genetic/epigenetic aberrations, the same processes that tightly control embryonic development, tissue regeneration, or wound healing are derailed in cancer.…”