Deconstructing and targeting aneuploidy in human cancer - Resubmission - 1

解构和靶向人类癌症中的非整倍性 - 重新提交 - 1

• 批准号: 10610814
• 负责人: Teresa Davoli
• 金额: $ 48.21万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610814
• 关键词: Adopted; Affect; Aneuploid Cells; Aneuploidy; Biological Markers; CRISPR screen; Cancer Patient; Cancer cell line; Candidate Disease Gene; Cell Death; Cell Line; Cell model; Cells; Cellular Stress; Chromosome 7; Chromosomes; Clinical; Clinical Research; Colon; Colorectal Adenocarcinoma; Colorectal Cancer; Colorectal Neoplasms; Complement; Data; Diploid Cells; Disease; Engineering; Event; FRAP1 gene; Foundations; Frequencies; Genes; Genetic; Genetic Transcription; Genomics; Goals; Human; Human Chromosomes; In Vitro; Knowledge; Malignant Neoplasms; Methods; Molecular; Normal tissue morphology; Oncogenic; Operative Surgical Procedures; Organoids; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Phenotype; Phosphoproteins; Proliferating; Property; Protein Inhibition; Protein Synthesis Inhibition; Proteins; Proteomics; Regulation; Role; Sampling; Signal Transduction; Solid Neoplasm; System; Testing; Translations; cancer cell; cancer therapy; candidate validation; cell type; chromosome 7 gain; cohort; colon cancer cell line; dosage; experimental study; improved; in vivo; mouse model; neoplastic cell; new therapeutic target; novel; overexpression; personalized cancer therapy; success; synthetic lethal interaction; therapeutic target; therapy resistant; tumor; tumor progression; tumorigenesis

Summary Aneuploidy—the presence of chromosome gains and losses—is very rare in normal tissues but occurs in more than 80% of human tumors, especially in solid tumors. A high level of aneuploidy in tumors correlates with higher- grade disease, tumor progression, and resistance to therapy. Whether and how aneuploidy contributes to formation and progression of human tumors is not well understood. Whereas genomic and clinical studies in cancer patients suggest that aneuploidy drives tumorigenesis, experimental studies in mouse models and in vitro systems has so far yielded conflicting data on the role of aneuploidy in tumors. Human tumors are often specifically associated with either increases or decreases in the number of specific chromosome(s). One of the main obstacles to progress has been the technical limitation of not being able to engineer the ‘right’ type of aneuploidy in the ‘right’ cell type. Our ultimate goal is to dissect whether and how aneuploidy contributes to initiation and progression or human tumors. Our first objective here is to generate cellular models that faithfully recapitulate the aneuploidy patterns found in tumors in order to study how aneuploidy affects the pathobiology of tumor cells (their ability to grow in vitro or in vivo, to evade cell death pathways, to survive cellular stress and to regulate transcription and translation). Our second objective is to uncover vulnerabilities and synthetic lethal interactions potentially associated with the aneuploid state. The outcomes of the proposed project will represent the foundation to achieve the long-term goal of our lab, which is to develop a better understanding of the causes and consequences of aneuploidy in human tumors in order to uncover aneuploidy-associated biomarkers and therapeutic targets. To accomplish this goal, we will first use a panel of newly generated human cells containing different degrees and types of aneuploidy to compare diploid and aneuploid cells for several tumor-related cellular phenotypes both in vitro and in vivo. Secondly, we will adopt a systematic approach to identify genes and pathways that when blocked, inhibit proliferation and survival of aneuploid tumor cells but not normal cells. Third, we will perform a protein and phospho-protein analysis mainly of colorectal tumor patients’ samples to dissect the consequences of aneuploidy at the level of protein stability and pathway regulation. Our results will fill an important gap of knowledge in our current understanding of how aneuploidy evolves during tumorigenesis and how we might take advantage of this knowledge to improve patient outcomes.

概括 非整倍性（染色体获得和丢失的存在）在正常组织中非常罕见，但在更多组织中发生 超过 80% 的人类肿瘤，尤其是实体瘤，肿瘤中的高水平非整倍性与较高的相关性相关。 疾病分级、肿瘤进展和治疗耐药性是否以及如何影响非整倍性。 在基因组和临床研究中，人类肿瘤的形成和进展尚不清楚。 癌症患者表明非整倍性驱动肿瘤发生，小鼠模型和体外实验研究 迄今为止，关于非整倍性在人类肿瘤中的作用，系统经常产生相互矛盾的数据。 与特定染色体之一的数量增加或减少特别相关。 进步的主要障碍是无法设计“正确”类型的技术限制 “正确”细胞类型中的非整倍性。 我们的最终目标是剖析非整倍性是否以及如何促进起始和进展或 我们的首要目标是生成忠实再现非整倍性的细胞模型。 肿瘤中发现的模式，以研究非整倍性如何影响肿瘤细胞的病理学（它们的能力） 在体外或体内生长，逃避细胞死亡途径，在细胞应激下生存并调节转录和 我们的第二个目标是发现潜在的漏洞和合成致命相互作用。 与非整倍体状态相关的拟议项目的结果将代表以下基础： 实现我们实验室的长期目标，即更好地了解原因和 非整倍性在人类肿瘤中的后果，以揭示非整倍性相关的生物标志物和 治疗目标。 为了实现这一目标，我们将首先使用一组新生成的人类细胞，其中包含不同的 非整倍性的程度和类型，以比较几种肿瘤相关细胞的二倍体和非整倍体细胞 其次，我们将采用系统的方法来鉴定基因和体内表型。 当通路被阻断时，会抑制非整倍体肿瘤细胞的增殖和存活，但不会抑制正常细胞。 我们将主要对结直肠肿瘤患者的样本进行蛋白质和磷蛋白分析以进行解剖 我们的结果将填补非整倍性在蛋白质稳定性和通路调控水平上的影响。 我们目前对非整倍体在肿瘤发生过程中如何进化的理解存在重要的知识空白 我们如何利用这些知识来改善患者的治疗结果。