Cancer Impact Area, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
JCI Insight. 2021 Feb 8;6(3):130510. doi: 10.1172/jci.insight.130510.
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.
不对称细胞分裂（ACD）使干细胞群能够维持，同时产生分化的后代。癌症干细胞（CSC）在肿瘤扩张和对治疗的反应中经历多种细胞分裂模式，但这些分裂模式的功能后果仍有待确定。我们使用一种荧光报告基因来检测细胞表面受体在有丝分裂过程中的分布，发现 ACD 产生了一个具有增强的治疗抗性的子细胞，并从神经胶质瘤 CSC 中增强了 EGFR 和神经营养因子受体（p75NTR）的共富集。同时刺激这两个受体拮抗了分化诱导，并促进了自我更新能力。p75NTR 的敲低增强了 EGFR 抑制的治疗效果，表明 p75NTR 和 EGFR 的共同遗传通过冗余机制促进了对 EGFR 抑制的抗性。这些数据表明，ACD 产生了具有共富集生长因子受体的后代，这有助于产生更具治疗抗性的 CSC 群体。
