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

不对称细胞分裂驱动胶质母细胞瘤的治疗抵抗和自我更新

• 批准号: 9305615
• 负责人: Masahiro Hitomi
• 金额: $ 7.93万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305615
• 关键词: Advanced Malignant Neoplasm; Biochemical; Biological; Cell Cycle; Cell Maintenance; Cell Separation; Cell division; Cell membrane; Cells; Cellular biology; Cholesterol; Cues; Data; Development; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Excision; Exposure to; Glioblastoma; Goals; Green Fluorescent Proteins; Growth; Growth Factor Receptors; Heterogeneity; Homeostasis; Image Analysis; Inherited; Instruction; Ligands; Maintenance; Malignant Neoplasms; Membrane Microdomains; Mitosis; Molecular; NGFR Protein; Natural regeneration; Operative Surgical Procedures; Oxygen; Pathway interactions; Play; Population; RNA Interference; Radiation; Reagent; Receptor Inhibition; Recurrence; Recurrent tumor; Reporter; Reporting; Resistance; Role; Signal Transduction; Signaling Molecule; Staining method; Stains; Stem cells; Stress; System; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; base; cancer stem cell; cancer survival; cancer therapy; cellular imaging; chemotherapy; daughter cell; effective therapy; improved; insight; multimodality; mutant; neoplastic cell; next generation; novel; novel strategies; novel therapeutic intervention; pluripotency; pressure; prevent; prospective; receptor; resistance mechanism; self-renewal; stem cell division; targeted treatment; temozolomide; therapy resistant; transcription factor; tumor; tumor growth; tumor initiation; tumor xenograft; tumorigenesis

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.

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 例如胶质母细胞瘤。胶质母细胞瘤用多模式方法治疗，包括手术切除， 放疗和化疗，但总的中位生存期仍然很短（15-18个月）。最近 研究发现了一种专门的自我更新肿瘤细胞亚群，称为癌症干细胞 肿瘤干细胞（CSC），具有增强的肿瘤起始能力，对许多肿瘤治疗剂具有抗性。是 因此，假设存活于抗癌治疗的CSC引起复发性肿瘤。确定新 制定更有效的治疗策略，了解CSC维持的机制 是必要的. CSC的维持是由它们所处的微环境的指导性线索调节的，类似于 未转化的体细胞体干细胞的命运受细胞分裂方式的调节。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着干细胞库，这是再生干细胞所必需的。 受损组织或用于补充细胞以维持组织稳态。我们的团队和其他人 证明CSC也不对称分裂，但这种细胞分裂的生物学重要性并不重要。 明白我们观察到，不对称细胞分裂共富集多种生长因子受体（GFR）， 一个子细胞 由于这些GFR激活了对CSC维持很重要的常见的多种下游效应物， 假设多个冗余受体的不对称遗传维持了自我更新， 在治疗压力下，一个子细胞的熟练程度以另一个为代价。为了验证这一 假设，我们建立了一个绿色荧光蛋白（GFP）为基础的报告系统，表明 GFR在真实的时间内的不对称遗传。使用这个系统，我们将研究：1） 在治疗剂存在下CSC维持中的不对称细胞分裂，和2）在治疗剂存在下CSC维持中的分子分裂， 这些共同遗传受体形成冗余信号网络以支持CSC的机制 上维护我们的长期目标是了解CSC中细胞不对称分裂的后果， 利用所获得的信息来增强包括胶质母细胞瘤在内的晚期癌症的治疗效果。