Functional Approaches to Understanding Cancer Aneuploidy: Interrogating the Effects of Chromosome 3p Deletion

项目摘要 研究 非整倍体，即整个染色体或染色体臂的获得或丢失，几乎是一种普遍的特征 癌症。然而，非整倍体在肿瘤发病机制中的作用仍然是一个悬而未决的问题。 生物学。肺鳞状细胞癌(SCC)非整倍体率较高。 肿瘤类型。对于肺鳞状细胞癌，与肺腺癌不同，目前几乎没有靶向治疗方法，因为 在肺鳞状细胞中发现的致癌突变较少。然而，SCC的特征是具有明显的 非整倍体事件的概况。特别是，染色体臂3p在几乎80%的肺鳞状细胞癌中丢失，这表明 它在这种肿瘤类型的肿瘤发生中起着重要作用，并可能成为有用的疾病靶点。 这一建议的目的是了解染色体3p缺失的表型效应以及 具有这种改变的癌细胞可以被特定地作为靶点。我们之前已经开发出了一个基因组 人肺上皮细胞染色体臂3p缺失的工程方法。接下来是这一点 模型系统，这项建议将采取三个互补的方法：(1)干扰素研究 在染色体3p缺失的细胞中信号上调，(2)细胞用来识别适应机制 克服染色体3p缺失导致的增殖缺陷，以及(3)系统的遗传筛选 确定特定于染色体3p缺失的依赖关系。通过确定染色体3p丢失对小鼠的影响 肺细胞，我们将深入了解患者特有的非整倍体如何促进肿瘤的发展。这些 研究还可能确定治疗鳞状细胞癌的新靶点。 应聘者的职业目标 我的长期目标是了解非整倍体和染色体不平衡在癌症发展中的作用。 作为一名独立的调查者，我想建立我的癌细胞生物学和分析 患者数据，结合实验和计算方法来研究非整倍体。K22奖将 请允许我从计算生物学家和其他合作者那里获得额外的培训，以执行 以独立调查者的身份进行拟议的实验。 环境 Dana-Farber癌症研究所拥有国际公认的基础和 翻译研究，包括免疫肿瘤学和癌症基因组学。此外，作为一个附属公司， 作为博德研究所的研究员，我将能够获得基因组测序服务和高通量 他们提供的筛查服务。我希望在一家有类似条件的研究机构获得教职。 这些机构的设施和智力环境。在获得终身教职后，我将 成立了一个由癌症研究人员组成的顾问委员会来监督我的职业发展。

Project Summary Research Aneuploidy, the gain or loss of whole chromosomes or chromosome arms, is a near-universal feature of cancer. However, the role of aneuploidy in tumor pathogenesis remains an unanswered question in cancer biology. Lung squamous cell carcinomas (SCCs) have a high rate of aneuploidy when compared to other tumor types. For lung SCC, unlike lung adenocarcinoma, few targeted therapies are currently available, as there are fewer oncogenic mutations identified in lung SCCs. However, SCCs are characterized by a distinct profile of aneuploidy events. In particular, chromosome arm 3p is lost in almost 80% of lung SCCs, suggesting it plays an important role in oncogenesis in this tumor type and may be a useful disease target. The goal of this proposal is to understand the phenotypic effects of chromosome 3p deletion and whether cancer cells with this alteration can be specifically targeted. We have previously developed a genome engineering approach to delete chromosome arm 3p in human lung epithelial cells. Following on with this model system, three complimentary approaches will be pursued in this proposal: (1) study of interferon signaling up-regulated in chromosome 3p deleted cells, (2) identification of adaptive mechanisms cells use to overcome proliferation defects induced by chromosome 3p deletion, and (3) systematic genetic screening to identify dependencies specific to chromosome 3p deletion. By determining the effect of chromosome 3p loss in lung cells, we will gain insights into how a patient-specific aneuploidy contributes to tumor development. These studies may also identify novel therapeutic targets for treatment of SCCs. Candidate Career Goals My long-term goal is to understand the role of aneuploidy and chromosome imbalance in cancer development. As an independent investigator, I want to build my research program on cancer cell biology and analysis of patient data, combining experimental and computational approaches to study aneuploidy. The K22 award will allow me to obtain additional training from computational biologists and other collaborators to perform the proposed experiments as an independent investigator. Environment The Dana-Farber Cancer Institute has internationally recognized research programs in both basic and translational research, including immuno-oncology and cancer genomics. In addition, as an affiliated researcher of the Broad Institute, I will have access to genome sequencing services and high-throughput screening services they provide. I expect to obtain a faculty position in a research institution that has similar facilities and intellectual environment as these institutions. After obtaining a tenure-track faculty position, I will put together an advisory committee of cancer researchers to oversee my career development.