Frequency and consequences of chromosome missegregation in breast cancer

乳腺癌染色体错误分离的频率和后果

• 批准号: 10362558
• 负责人: Andrew Lynch
• 金额: $ 3.38万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362558
• 关键词: Abnormal Cell; Acute; Address; Aneuploidy; Biological; Biological Assay; Breast Cancer Patient; Breast Cancer cell line; Cancer Biology; Cell Death; Cell Line; Cell division; Cell model; Cell physiology; Cells; Cellular biology; Chemicals; Chromosomal Instability; Chromosomal Rearrangement; Chromosome Segregation; Chromosomes; Clinical; Communication; Communities; Complex; Computer Models; Core Biopsy; Cytogenetics; DNA sequencing; Data; Evolution; Frequencies; Gene Expression Profile; Generations; Genetic Models; Genetic Transcription; Genomics; Goals; Harvest; Heterogeneity; Human; Incidence; Institution; Karyotype; Karyotype determination procedure; Knowledge; Malignant Neoplasms; Mammalian Cell; Mammary Neoplasms; Measures; Methods; Microscopic; Modeling; Mutation; Organoids; Outcome; Paclitaxel; Patients; Pattern; Positioning Attribute; Process; Prognostic Marker; Recording of previous events; Research; Research Personnel; Research Project Summaries; Resolution; Role; Solid Neoplasm; Tetracyclines; Time; Tissues; Training; Transcription Alteration; Transcription Process; Work; Yeasts; analytical method; biological adaptation to stress; breast cancer progression; cancer genomics; cancer therapy; career; chemotherapy; chromosome loss; chromosome missegregation; clinically significant; computer framework; design; experience; genome sequencing; improved; innovation; insight; malignant breast neoplasm; member; multidisciplinary; multimodality; patient prognosis; patient response; pressure; programs; response; single cell sequencing; skills; taxane; transcriptome sequencing; transcriptomics; tumor; tumor heterogeneity

PROJECT SUMMARY Research. Chromosomal instability (CIN) – observed as the first cancer hallmark over 100 years ago – is characterized by the persistent loss and gain of whole chromosomes through abnormal cell division. This process results in aneuploidy, the state of having an incorrect number of chromosomes, which is present in over 70% of solid tumors, some of which display recurring patterns of aneuploidy. Persistent ‘missegregation’ of chromosomes is associated with worse patient prognosis and advanced clinical features. This is attributed to the increased adaptability of a tumor having increased genomic diversity via a broad landscape of different aneuploid clones. At higher rates of missegregation it appears to cause cell death and tumor inhibition. The occurrence of CIN is also theorized to sensitize tumors to CIN-inducing chemotherapies like taxanes. Despite CIN’s long history, its clinical use as a prognostic marker and biomarker for taxane efficacy is inaccessible as current methods of quantifying rates of chromosome missegregation are either infeasible in tissue, insufficiently informative and/or labor intensive. A critical goal for this proposal to combine stochastic computational modeling of cell division with single cell sequencing of tumors in order to allow for the quantification of intratumoral rates of chromosome missegregation. Additionally, cellular processes after chromosome missegregation that underlie karyotypic selection have not been explored. We hypothesize that post- missegregation transcriptional processes either preclude or permit the propagation of clones with specific aneuploid chromosome combinations. We will stochastically generate many combinations of chromosome copy number alterations in transformed and non-transformed cell lines and analyze the acute transcriptional alterations and clonal composition at single cell resolution. Overall, the long-term goal for this proposal is to resolve the complex relationship between chromosome missegregation and breast cancer progression with respect to its incidence in human breast tumors and downstream transcriptional consequences that underlie tumor evolution. This work is innovative in its approach and will significantly improve our understanding of tumor evolution and how to evaluate CIN in patients. Training. Through completion of the proposed research, I will develop my skills in the design and implementation of high impact and rigorous scientific studies. Through coursework and interactions with lab members and collaborators, I will develop multi-disciplinary expertise in cell biological and genomics/transcriptomics experimental and analytical methods. I will hone professional skills in scientific communication, public engagement, and networking through the many opportunities afforded to me to interact with and present my research to collaborators, field-experts, legislators, and community members. The unique, multi-disciplinary training proposed here will position me well for a career as an independent investigator in the field of cancer genomics at an academic or federal research institution.

项目概要 研究发现，染色体不稳定性（CIN）是 100 多年前第一个癌症标志。 其特征是通过异常细胞分裂持续丢失和获得整个染色体。 导致非整倍体，即染色体数量不正确的状态，超过 70% 的染色体都存在这种情况 实体瘤，其中一些表现出持续的非整倍性“错误分离”模式。 染色体与较差的患者预后和先进的临床特征相关。 通过广泛的不同非整倍体，增加基因组多样性的肿瘤的适应性 在较高的错误分离率下，它似乎会导致细胞死亡和肿瘤抑制的发生。 理论上 CIN 也会使肿瘤对紫杉烷等 CIN 诱导化疗敏感，尽管 CIN 的时间很长。 历史上，其作为紫杉烷疗效的预后标志物和生物标志物的临床应用是目前无法实现的 量化染色体错误分离率的方法在组织中要么不可行，要么不充分 该提案的一个关键目标是结合随机计算。 通过肿瘤的单细胞测序建立细胞分裂模型，以便定量 此外，染色体错误分离的瘤内率。 核型选择背后的错误分离尚未被探索。 错误分离的转录过程要么阻止要么允许克隆的繁殖 我们将随机生成许多特定的非整倍体染色体组合。 转化和非转化细胞系的染色体拷贝数变化并分析急性 总体而言，这是该项目的长期目标。 该提案旨在解决染色体错误分离与乳腺癌之间的复杂关系 关于其在人类乳腺肿瘤中的发生率和下游转录 这项工作在方法上是创新的，并且将显着影响肿瘤进化的后果。 提高我们对肿瘤进化以及如何评估患者 CIN 的理解。 培训通过完成拟议的研究，我将发展我的设计和实施技能。 通过课程作业以及与实验室成员的互动，进行高影响力和严格的科学研究。 合作者，我将发展细胞生物学和基因组学/转录组学方面的多学科专业知识 我将磨练科学传播、公共领域的专业技能。 通过为我提供的许多机会与人互动并展示我的 合作者、领域专家、立法者和社区成员的研究 独特的、多学科的。 这里提出的培训将使我成为该领域的独立调查员的职业生涯 学术或联邦研究机构的癌症基因组学。