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: 9720378
• 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/9720378
• 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; 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.

项目摘要 研究 非整倍性是整个染色体或染色体臂的增益或损失，是几乎全宇宙的特征 癌症。然而，非整倍性在肿瘤发病机理中的作用仍然是癌症中未解决的问题 生物学。与其他相比 肿瘤类型。对于肺SCC，与肺腺癌不同，目前很少有靶向疗法，因为 肺SCC中发现的致癌突变较少。但是，SCC的特征是独特的 非整倍性事件的轮廓。特别是，近80％的肺SCC丢失了染色体ARM 3P，这表明 它在这种肿瘤类型的肿瘤发生中起着重要作用，可能是有用的疾病靶标。 该提案的目的是了解3P染色体缺失的表型效应以及是否是否 具有这种改变的癌细胞可以是针对目标的。我们以前已经开发了一个基因组 在人肺上皮细胞中删除染色体ARM 3P的工程方法。跟随此 模型系统，将在此提案中采用三种免费方法：（1）干扰素研究 在3P染色体上删除细胞中上调的信号传导（2）鉴定自适应机制细胞用于 克服由3p染色体删除引起的增殖缺陷，（3）系统遗传筛查至 确定特定于3P染色体删除的依赖性。通过确定3P染色体损失的影响 肺部细胞，我们将深入了解患者特异性的非整倍性如何对肿瘤发育有效。这些 研究还可以鉴定出用于治疗SCC的新型治疗靶标。 候选职业目标 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，我想构建有关癌细胞生物学的研究计划和分析 患者数据，结合了研究非整倍性的实验和计算方法。 K22奖将 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来执行 提出的作为独立研究者的实验。 环境 达纳 - 法伯癌症研究所（Dana-Farber Cancer Institute）在基本和 翻译研究，包括免疫肿瘤和癌症基因组学。另外，作为附属 Broad Institute的研究人员，我将可以访问基因组测序服务和高通量 他们提供的筛选服务。我希望在具有类似的研究机构中获得教师职位 设施和智力环境作为这些机构。在获得任期教师职位后，我将 组建一个癌症研究人员咨询委员会，以监督我的职业发展。