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

了解癌症非整倍性的功能方法：探究染色体 3p 缺失的影响

• 批准号: 10066326
• 负责人: Alison M. Taylor
• 金额: $ 19.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066326
• 关键词: Advisory Committees; Aneuploidy; Automobile Driving; Basic Science; Biological Assay; Biological Models; Bladder; CRISPR screen; Cancer Biology; Cancer cell line; Cell Line; Cells; Cellular biology; Chromosome 3; Chromosome Arm; Chromosome abnormality; Chromosomes; Coculture Techniques; Dana-Farber Cancer Institute; Data; Data Set; Defect; Dependence; Development; Disease; Environment; Epithelial Cells; Esophagus; Event; Faculty; Gene Expression; Genes; Genetic; Genetic Screening; Genome engineering; Genomics; Goals; Growth; Human; Human Characteristics; Immune; Immune signaling; Immunooncology; In Vitro; Individual; Institutes; Institution; Interferons; International; K22 Award; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Mutation; Oncogenic; Pathogenesis; Patients; Pattern; Phenotype; Play; Positioning Attribute; Research; Research Personnel; Research Project Summaries; Role; Services; Signal Pathway; Signal Transduction; Squamous Cell Lung Carcinoma; Squamous cell carcinoma; System; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tissues; Training; Translational Research; Yeasts; arm; base; cancer cell; cancer genomics; cancer subtypes; career; career development; chromosome 3p loss; chromosome 3q gain; chromosome loss; cytokine; exome sequencing; experimental study; genome sequencing; genome-wide; high throughput screening; insight; knock-down; new therapeutic target; programs; screening services; targeted treatment; tenure track; tumor; tumor progression; tumorigenesis

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.

项目概要 研究 非整倍性，即整个染色体或染色体臂的获得或丢失，是近乎普遍的特征 癌症。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悬而未决的问题 生物学。与其他癌症相比，肺鳞状细胞癌 (SCC) 的非整倍性比例较高 肿瘤类型。对于肺鳞状细胞癌，与肺腺癌不同，目前可用的靶向治疗很少， 肺鳞状细胞癌中发现的致癌突变较少。然而，SCC 的特点是具有独特的 非整倍体事件概况。特别是，近 80% 的肺 SCC 中染色体臂 3p 丢失，表明 它在这种肿瘤类型的肿瘤发生中发挥着重要作用，并且可能是一个有用的疾病靶点。 该提案的目标是了解染色体 3p 缺失的表型效应以及是否 具有这种改变的癌细胞可以被专门靶向。我们之前已经开发了一个基因组 删除人肺上皮细胞中染色体臂3p的工程方法。继此 模型系统，本提案将采用三种补充方法：（1）干扰素研究 染色体 3p 缺失细胞中信号传导上调，(2) 识别细胞用于适应的机制 克服染色体 3p 缺失引起的增殖缺陷，以及 (3) 系统的遗传筛查 识别特定于染色体 3p 缺失的依赖关系。通过确定染色体 3p 丢失的影响 肺细胞，我们将深入了解患者特异性非整倍性如何促进肿瘤发展。这些 研究还可能确定治疗鳞状细胞癌的新治疗靶点。 候选人的职业目标 我的长期目标是了解非整倍性和染色体失衡在癌症发展中的作用。 作为一名独立研究者，我想建立关于癌细胞生物学和分析的研究计划 患者数据，结合实验和计算方法来研究非整倍性。 K22奖将 让我从计算生物学家和其他合作者那里获得额外的培训来执行 作为独立研究者提出的实验。 环境 丹娜—法伯癌症研究所在基础和癌症领域拥有国际认可的研究项目。 转化研究，包括免疫肿瘤学和癌症基因组学。此外，作为附属 作为布罗德研究所的研究员，我将可以获得基因组测序服务和高通量 他们提供的筛查服务。我希望在具有类似条件的研究机构中获得教职 设施和智力环境与这些机构相同。在获得终身教授职位后，我将 组建了一个由癌症研究人员组成的咨询委员会来监督我的职业发展。