Molecular Basis and Role of Indirect Chromosome Segregation in Hyperploid Cancer Cells

超倍体癌细胞中间接染色体分离的分子基础和作用

• 批准号: 9315607
• 负责人: Christina Lynn Hueschen
• 金额: $ 3.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315607
• 关键词: Ablation; Adaptor Signaling Protein; Adverse effects; Alpha Cell; Anaphase; Aneuploid Cells; Aneuploidy; Architecture; Binding; Breast; Breast Adenocarcinoma; Breast Cancer Cell; Cancer Etiology; Cell Death; Cell Line; Cell Survival; Cell physiology; Cells; Cellular biology; Chemotherapy-Oncologic Procedure; Chromosomal Instability; Chromosome Segregation; Chromosomes; Complex; Confocal Microscopy; Crowding; Development; Diploid Cells; Diploidy; Dynein ATPase; Etiology; Fiber; Goals; Human; Image; Immunofluorescence Immunologic; Investigation; Kinetics; Laboratories; Lasers; Length; Malignant Neoplasms; Mammary gland; Measures; Mechanics; Mediating; Microscopy; Microtubule Bundle; Microtubules; Minus End of the Microtubule; Mitosis; Mitotic spindle; Modeling; Molecular; Molecular Target; Motor; Mutation; Oncogenic; Paclitaxel; Patients; Play; Ploidies; Quality of life; Recruitment Activity; Resolution; Role; Staining method; Stains; Testing; Therapeutic; Time; Walking; Work; cancer cell; cellular imaging; daughter cell; dynactin; genetic information; killings; new therapeutic target; novel; novel therapeutics; preference; public health relevance; segregation; targeted cancer therapy; therapy development; tool; tumor

 DESCRIPTION (provided by applicant): Hyperploidy (cells with abnormally high numbers of chromosomes) is observed in most human cancers and has been recognized as a hallmark of cancer cells for over a century. The association between hyperploidy and cancer is clear, and provides a clear therapeutic opportunity. If we can identify cellular processes strained or altered by hyperploidy, we can in principle develop therapies that specifically target hyperploid tumors. Currently, standard cancer chemotherapy agents such as taxol (paclitaxel) indiscriminately target dividing cells, causing myriad side effects that limit their efficacy and reduce patient quality of life. New cancer chemotherapies are needed, with greater selectivity for cancer cells. To perform its function, the mitotic spindle of a hyperploid cancer cell must align and segregate as many as four times the normal number of chromosomes. Hyperploid spindles are crowded with extra chromosomes and extra k-fibers (the bundles of microtubules that hold on to chromosomes), resulting in altered spindle architecture. Interestingly, not all k-fibers in hyperploid human cancer cells are directly connected to the spindle pole (Sikirzhytski* and Magidson* et al., 2014). Our laboratory recently discovered that chromosomes that lack a direct connection to the spindle pole can still undergo segregation via an alternative - now indirect - transport mechanism, mediated by the dynein-dynactin motor complex and the dynein adaptor protein NuMA (Elting* and Hueschen* et al., 2014). Here, we propose to investigate this newly- uncovered alternative mechanism of chromosome segregation and the role it plays in hyperploid cancer cells. We hypothesize that hyperploid cancer cells are preferentially dependent on this indirect chromosome segregation mechanism, and propose to investigate its underlying cellular biology with the goal of uncovering novel therapeutic targets and strategies. Specifically, we aim to identify the molecular mechanism of indirect chromosomes segregation and to determine if hyperploid cancer cells are preferentially dependent on indirect chromosome segregation for survival. Our strategy combines: spindle laser ablation as a tool to create indirect chromosome-to-pole connections, molecular perturbations and readouts, and high resolution microscopy of both non-transformed diploid cells and breast cancer cells of different ploidy. We expect that our investigation of the molecular mechanism of indirect chromosome segregation will reveal novel targets for cancer therapy. Moreover, we expect that uncovering the role of indirect segregation in hyperploid cell function will determine the potential for selective hyperploid cell death by indirect segregation inhibition, alone or in combination with existing cancer chemotherapies. In the long term, this work may contribute to the development of novel and selective cancer chemotherapies.

 描述（由应用提供）：在大多数人类癌症中观察到多倍性（具有绝对高染色体的细胞），并且已被认为是癌细胞的标志，已有一个多世纪的历史。多倍性与癌症之间的关联很明显，并提供了明显的治疗机会。如果我们可以识别狭窄或改变的细胞过程 通过过倍性，我们可以原则上开发特异性靶向多倍性肿瘤的疗法。目前，标准的癌症化学疗法剂（如紫杉醇（紫杉醇））不加选择地针对分裂细胞，从而导致无数副作用，从而限制其有效性并降低患者的生活质量。需要新的癌症化学疗法，对癌细胞具有更大的选择性。为了执行其功能，多倍性癌细胞的有丝分裂纺锤必须对齐并隔离染色体数量的四倍。多倍体纺锤体挤满了额外的染色体和额外的K纤维（固定在染色体上的微管束），导致纺锤体架构的改变。有趣的是，并非所有具有多倍型人类癌细胞中的K纤维直接连接到纺锤极（Sikirzhytski*和Magidson*等，2014）。我们的实验室最近发现，我们假设多倍性癌细胞更有可能依赖于这种间接染色体分离机制的染色体，并建议研究其潜在的细胞生物学，目的是揭示新的治疗靶标和策略。具体而言，我们旨在确定间接染色体分离的分子机制，并确定多倍性癌细胞是否优选依赖于间接染色体分离以进行生存。我们的策略结合了：纺锤激光消融作为创建间接染色体与极点连接，分子扰动和读数的工具，以及对非转化的二倍体细胞和不同倍序的乳腺癌细胞的高分辨率显微镜。我们预计我们对间接染色体分离的分子机制的研究将揭示癌症治疗的新靶标。此外，我们期望发现间接分离在多倍性细胞功能中的作用将确定通过单独或与现有癌症化学疗法结合的间接分离抑制选择性多倍性细胞死亡的潜力。从长远来看，这项工作可能有助于新型和选择性癌症化学疗法的发展。