Mechanisms of cell proliferation in whole-genome doubled cells

非计划全基因组加倍事件(WGD)导致与人类相关的多倍体细胞 疾病。最重要的是，WGD产生了遗传不稳定的四倍体细胞，可以促进肿瘤的发生。 最近的计算分析显示，近40%的实体肿瘤至少经历过一次 WGD，通常是在其发展的早期，表明这种事件在两个启动过程中都发挥着重要作用 和/或人类恶性肿瘤的进展。通过以下途径全面了解这些机制 因此，哪个全基因组加倍的细胞产生并促进肿瘤的发生是关键的，尽管在很大程度上 细胞生物学的未知领域。这项提案的目标是将计算、细胞生物学和动物 用模型方法学检验总体假设，即全基因组加倍的细胞必须获得特定的 基因适应，使它们能够容忍DNA含量加倍带来的众多缺陷，以及 这些细胞因此被赋予了正常二倍体所不存在的特定的遗传依赖性 细胞(即倍性特有的致死性)。这些假设将在三个具体目标上得到检验。目标1：使用 快速定量体内不同组织中WGD的频率和潜在原因的创新方法 并确定这一频率是否受年龄的影响。目的2：验证编码有丝分裂激动素的KIF18A， 作为体内倍体特异的致死基因，并使用等基因二倍体/四倍体细胞模型进行成像- 基于表型筛选鉴定KIF18A的小分子抑制剂。目标3：确定遗传变异(例如 基因扩增/缺失)，这些基因在全基因组加倍的肿瘤中显著和特异地丰富， 并从机制上定义了这种改变如何在体外和体内提供倍性特有的生长优势。 这些目标的成功完成将为我们提供对生物起源、生物学和进化的重要洞察。 全基因组加倍的细胞，以及潜在地揭示新的和创新的治疗途径 杀死全基因组加倍的癌细胞，同时保留它们产生的正常健康的二倍体。

Unscheduled whole-genome doubling events (WGD) give rise to polyploid cells that are associated with human disease. Most significantly, WGD generates genetically unstable tetraploid cells that can fuel tumorigenesis. Recent computational analyses have revealed that nearly 40% of all solid tumors have undergone at least one WGD, often early in their development, demonstrating that such events play significant roles in both the initiation and/or progression of human malignancies. Gaining a comprehensive understanding of the mechanisms through which whole-genome doubled cells arise and promote tumorigenesis is therefore a critical, albeit largely unexplored area of cell biology. The goal of this proposal is to combine computational, cell biological, and animal model methodologies to test the overarching hypothesis that whole genome-doubled cells must acquire specific genetic adaptations that enable them to tolerate the numerous defects imparted by doubled DNA content, and that these cells are therefore imparted with specific genetic dependencies that are not present in normal diploid cells (i.e. ploidy-specific lethality). These hypotheses will be tested in three specific aims. Aim 1: Use an innovative approach to rapidly quantitate the frequency and underlying cause of WGD in different tissues in vivo and determine if this frequency is affected by aging. Aim 2: Validate KIF18A, which encodes for a mitotic kinesin, as a ploidy-specific lethal gene in vivo, and use isogenic diploid/tetraploid cell models to perform an imaging- based phenotypic screen to identify small molecule inhibitors of KIF18A. Aim 3: Identify genetic aberrations (e.g. gene amplifications/deletions) that are significantly and specifically enriched in whole genome-doubled tumors, and mechanistically define how such alterations provide ploidy-specific growth advantages in vitro and in vivo. Successful completion of these aims will provide significant insight into the genesis, biology, and evolution of whole-genome doubled cells, as well as potentially reveal new and innovative therapeutic avenues to selectively kill whole-genome doubled cancer cells while sparing the normal healthy diploids from which they arose.