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 - 染色体增长和损失的存在 - 在正常组织中非常罕见，但发生在更多 超过80％的人类肿瘤，尤其是在实体瘤中。肿瘤中高水平的非整倍性与较高的 等级疾病，肿瘤进展和对治疗的抵抗力。非整倍性是否有助于 人类肿瘤的形成和进展尚不清楚。而基因组和临床研究 癌症患者表明，非整倍性驱动肿瘤发生，小鼠模型中的实验研究和体外 到目前为止，已经对非整倍性在肿瘤中的作用产生了矛盾的数据。人类肿瘤通常是 特异性染色体数量的增加或减少是特别相关的。中的一个 进步的主要障碍是无法设计“正确”类型的技术限制 “右”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主动性和进步或 人类肿瘤。我们的第一个目标是生成忠实地概括非整倍性的细胞模型 在肿瘤中发现的模式是为了研究各个非整倍性如何影响肿瘤细胞的病理生物学（它们的能力 在体外或体内生长，以逃避细胞死亡途径，在细胞胁迫下生存并调节转录和 翻译）。我们的第二个目标是潜在地发现脆弱性和综合致命相互作用 与非整倍体状态相关。拟议项目的结果将代表基础 实现我们实验室的长期目标，即对原因和原因有更好的理解 人类肿瘤中非整倍性的后果是为了发现非整倍性相关的生物标志物和 治疗靶标。 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，其中包含不同的人类细胞 非整倍性的程度和类型，比较几个肿瘤相关细胞的二倍体和非整倍体细胞 体外和体内表型。其次，我们将采用一种系统的方法来识别基因和 阻塞后，抑制非整倍体肿瘤细胞而不是正常细胞的途径。第三， 我们将进行主要的结直肠肿瘤患者样品的蛋白质和磷酸蛋白质分析 非整倍性在蛋白质稳定性和途径调节水平上的后果。我们的结果将填补 在我们目前对肿瘤发生过程中各个非整倍性演变和 我们如何利用这些知识来改善患者的结果。