Mechanistic Elaboration of Fragility in the Cancer Cell Mitotic Spindle

描述（由申请人提供）：癌细胞采用复杂和多样的分子机制来克服通常防止失控增殖的先天屏障[1]。为了直接解决这一复杂性，我们率先应用全基因组siRNA筛选来鉴定那些基因产物，其缺失对非小细胞肺癌细胞（NSCLC）中的紫杉醇敏感性具有最显著的影响。这项工作发现了一系列不同的候选人，其中许多人似乎是异常基因表达程序的产物，只影响肿瘤细胞的有丝分裂。使用严格的客观统计算法和实验验证，我们已经确定了3个新的和功能多样的基因，其在有丝分裂中的作用还没有以前的特点。由于这些基因中的许多在肿瘤中显示出升高的表达模式，我们假设它们可能是细胞周期进展的肿瘤细胞特异性依赖性。该建议的目的是这些基因的功能的机制阐述，就其对体内有丝分裂和肿瘤生长的影响而言。这项工作的长期目标是解构肿瘤细胞有丝分裂所需的独特成分。最终，了解这些蛋白质如何支持有丝分裂将为治疗干预开辟新的途径。

DESCRIPTION (provided by applicant): Cancer cells employ complex and multifarious molecular mechanisms to overcome innate barriers that normally prevent runaway proliferation[1]. To address this complexity directly, we have pioneered the application of genome-wide siRNA screening to identify those gene products whose depletion has the most significant impact on paclitaxel sensitivity in Non-Small Cell Lung Cancer cells (NSCLC). This effort uncovered a collection of diverse candidates many of whom appear to be the products of anomalous gene expression programs and only impact mitosis in tumor cells. Using a stringent objective statistical algorithm and experimental validation, we have identified 3 novel and functionally diverse genes, whose role in mitosis has not previously been characterized. Because many of these genes display elevated expression patterns in tumors, we hypothesize that they may be tumor-cell specific dependencies for cell cycle progression. The purpose of this proposal is the mechanistic elaboration of the function of these genes with respect to their impact on mitosis and tumor growth in vivo. The long-term objective of this work is to deconstruct the components that are uniquely required for tumor cell mitosis. Ultimately, an understanding of how these proteins support mitosis will open new avenues for therapeutic intervention.