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

项目摘要 研究 非整倍性，即整个染色体或染色体臂的获得或丢失，是染色体的一个几乎普遍的特征。 癌然而，非整倍体在肿瘤发病机制中的作用在癌症中仍然是一个未解之谜 生物学肺鳞状细胞癌（SCC）与其他恶性肿瘤相比， 肿瘤类型对于肺SCC，与肺腺癌不同，目前几乎没有靶向治疗，因为 在肺SCC中鉴定的致癌突变较少。然而，SCC的特征在于 非整倍性事件的概况。特别是，染色体臂3 p在几乎80%的肺SCC中丢失，表明 它在这种肿瘤类型的肿瘤发生中起重要作用，并且可能是有用的疾病靶点。 这项提议的目的是了解染色体3 p缺失的表型效应，以及是否 具有这种改变的癌细胞可以被特异性地靶向。我们之前已经开发了一个基因组 人肺上皮细胞染色体臂3 p缺失的工程方法接下来 模型系统，三个互补的方法将在本建议中进行：（1）干扰素的研究 在染色体3 p缺失的细胞中信号上调，（2）鉴定细胞用于 克服染色体3 p缺失导致的增殖缺陷，以及（3）系统的遗传筛选， 鉴定特异于染色体3 p缺失的依赖性。通过确定染色体3 p丢失在 肺细胞，我们将深入了解患者特异性非整倍体如何促进肿瘤发展。这些 研究还可以鉴定用于治疗SCC的新的治疗靶点。 候选人职业目标 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。 作为一个独立的研究者，我想建立我的研究计划，对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奖项将 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， 作为一名独立的研究者进行实验。 环境 丹娜-法伯癌症研究所拥有国际公认的基础和 转化研究，包括免疫肿瘤学和癌症基因组学。此外，作为一个 布罗德研究所的研究员，我将有机会获得基因组测序服务和高通量 他们提供的筛选服务。我希望能在一家有类似职位的研究机构谋得教职。 设施和智力环境。获得终身教职后，我将 组建了一个癌症研究人员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.