Mechanistic Elaboration of Fragility in the Cancer Cell Mitotic Spindle

描述（由申请人提供）：癌细胞利用复杂多样的分子机制来克服通常阻止失控增殖的先天屏障。为了直接解决这一复杂性，我们开创了全基因组siRNA筛选的应用，以鉴定那些缺失对非小细胞肺癌细胞（NSCLC）紫杉醇敏感性影响最大的基因产物。这项工作揭示了一系列不同的候选基因，其中许多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个新的和功能不同的基因，它们在有丝分裂中的作用以前没有被描述过。因为许多这些基因在肿瘤中表现出升高的表达模式，我们假设它们可能是肿瘤细胞对细胞周期进展的特异性依赖。本研究的目的是对这些基因在体内对有丝分裂和肿瘤生长的影响进行机制阐述。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.