Asymmetric cell division drives therapeutic resistance and self-renewal in glioblastoma

摘要 治疗耐药和肿瘤复发是晚期恶性肿瘤治疗的主要障碍 比如胶质母细胞瘤。胶质母细胞瘤的治疗采用多模式方法，包括手术切除， 放射治疗和化疗，但总体中位生存期仍然很短(15-18个月)。近期 研究确定了一种特殊的自我更新的肿瘤细胞亚群，称为癌症干细胞 (CSCs)，具有增强的肿瘤启动能力，对许多肿瘤治疗药物具有抗药性。它是 因此推测CSCs在抗癌治疗中存活会导致肿瘤复发。要确定新的 开发更有效治疗方法的策略，了解维持CSCs的机制 是必要的。 CSC的维护由它们所在的微环境中的指导性提示来调节，类似于 未转化的体细胞干细胞。体细胞的命运受细胞分裂方式的影响。一个 不对称细胞分裂维持自我更新的干细胞，同时产生一个分化的干细胞 子细胞。这种分裂模式维持干细胞储存库，这是再生干细胞所必需的 损伤组织或用于补充细胞以维持组织动态平衡。我们的团队和其他人 证明了CSCs也不对称分裂，但这种细胞分裂的生物学重要性并不是 明白了。我们观察到，细胞不对称分裂共同富含多个生长因子受体(GFRs)以 其中一个子细胞。 由于这些GFR激活了共同的多个下游效应器，这些效应器对CSC维护非常重要，我们 假设多个冗余受体的不对称遗传维持自我更新 在治疗压力下，其中一个子细胞的熟练程度以牺牲另一个细胞为代价。为了测试这一点 假设，我们建立了一个基于绿色荧光蛋白(GFP)的报告系统，表明 实时非对称继承GFRs。利用这个系统，我们将研究：1)生物作用 在治疗试剂存在下CSC维持中的不对称细胞分裂和2)分子 这些共同继承的受体形成冗余信号网络以支持CSC的机制 维修。我们的长期目标是了解CSCs细胞不对称分裂的后果，并 利用所获得的信息来提高包括胶质母细胞瘤在内的晚期癌症的治疗效果。

ABSTRACT Therapeutic resistance and tumor recurrence are major barriers to treatment for advanced malignant tumors such as glioblastoma. Glioblastoma is treated with a multimodal approach consisting of surgical resection, radiation, and chemotherapy, yet the overall median survival remains very short (15-18 months). Recent studies identified a specialized self-renewing subpopulation of neoplastic cells, termed cancer stem cells (CSCs), with enhanced tumor initiation capacity that are resistant to many tumor treatment agents. It is therefore postulated that the CSCs surviving anti-cancer therapy give rise to recurrent tumors. To identify new strategies to develop more effective therapies, understanding the mechanisms by which CSCs are maintained is necessary. CSC maintenance is regulated by instructive cues from the microenvironment in which they reside, similarly to untransformed somatic stem cells. The fate of somatic stem cells is regulated by the mode of cell division. An asymmetric cell division maintains a self-renewing stem cell while simultaneously generating one differentiated daughter cell. This mode of division maintains the stem cell reservoir, which is required for regeneration of damaged tissue or for replenishment of cells to maintain tissue homeostasis. Our group and others have demonstrated that CSCs also divide asymmetrically, yet the biological importance of this cell division is not understood. We observed that asymmetric cell division co-enriches multiple growth factor receptors (GFRs) to one of the daughter cells. As these GFRs activate common multiple downstream effectors that are important for CSC maintenance, we hypothesized that the asymmetric inheritance of multiple redundant receptors maintains the self-renewal proficiency of one of the daughter cells at the expense of the other under therapeutic pressure. To test this hypothesis, we established a green fluorescent protein (GFP)-based reporter system that indicates the asymmetric inheritance of GFRs in real time. Using this system, we will investigate: 1) the biological role of asymmetric cell division in CSC maintenance in the presence of therapeutic reagents and 2) the molecular mechanisms through which these co-inherited receptors form redundant signaling networks to support CSC maintenance. Our long-term goal is to understand the consequence of asymmetric cell division in CSCs and to utilize the obtained information to enhance the treatment efficacy of advanced cancers including glioblastoma.