Single cell analysis of the evolving mutational landscape in carcinogen exposed skin

对暴露于致癌物的皮肤中不断演变的突变景观的单细胞分析

• 批准号: 10674848
• 负责人: Eve Kandyba
• 金额: $ 10.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-11 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674848
• 关键词: Address; Automobile Driving; Biological Assay; Biological Models; Cancer Burden; Carcinogen exposure; Carcinogens; Cell Compartmentation; Cells; Chemical Agents; Chemical Exposure; Chemicals; Clonal Expansion; DNA Sequence Alteration; DNA sequencing; Development; Dorsal; Early Diagnosis; Epithelium; Exposure to; Foundations; Genetic; Genetic Anticipation; Homeostasis; Individual; Injury; Intestines; Knowledge; Lung; Malignant Neoplasms; Mus; Mutate; Mutation; Normal tissue morphology; Pattern; Population; Predisposition; Skin; System; Time; Tissues; carcinogenicity; human tissue; in vivo; regeneration model; regenerative; sequencing platform; single cell analysis; single cell sequencing; stem cell population; stem cells; tissue repair; tumor; tumorigenesis

Abstract The development of early detection approaches is fundamental to reduce the growing cancer burden. Cellular accumulation of genetic mutations is believed to be the foundation of tumor development, however, there is a fundamental lack of knowledge regarding the earliest stages of tumorigenesis and whether certain cell populations may be more predisposed to acquire initial driving mutations. Stem cells are long-lived cells which reside in tissues and serve as a regenerative pool that actively maintain normal homeostasis and can repair tissue after injury. Accumulating evidence indicates that stem cells may also serve as the cells of origin for tumorigenesis in certain tissues and generate clonal expansions of mutated cells which could be more susceptible to further genetic insults over time. As it is not feasible to address the evolving mutational burden of stem cells in tissues of human individuals, this study will exploit mouse dorsal skin, a highly informative regenerative model system with well characterized and distinct stem cell populations. The dynamic mutation co-occurrence profiles of specific skin mouse stem cell populations will be determined following exposure to known carcinogens utilizing a customizable, single cell DNA-sequencing platform. This approach will identify whether certain mutational profiles are selectively enriched and tolerated in specific stem cell populations over long periods of time in functionally normal tissue following carcinogen exposure. The approach used by this study could easily be adapted to screen many different chemical exposures and has the potential to detect the earliest signs of cancer in similar epithelial tissue systems with shared stem cell populations such as the lung and intestine – which are often exposed to long term environmental and chemical insult - before tumors are evident and determine distinct carcinogen-exposure signatures in cells.

抽象的 早期检测方法的发展对于减少癌症的生长至关重要 负担。据信遗传突变的细胞积累是肿瘤的基础 但是，发展基本上缺乏有关最早阶段的知识 肿瘤发生以及某些细胞种群是否可能更容易获得初始 驾驶突变。干细胞是长期寿命的细胞，驻留在组织中，并用作 再生池，可积极维持正常的体内平衡，并且可以在受伤后修复组织。 积累的证据表明干细胞也可能充当原始细胞 某些组织中的肿瘤发生并产生突变细胞的克隆膨胀，这可能是 随着时间的流逝，更容易受到进一步的遗传侮辱。因为解决不断发展的不可行 干细胞在人体组织中的突变烧伤，这项研究将利用小鼠背侧 皮肤，一种信息丰富的再生模型系统，具有良好的特征和独特的干细胞 人群。特定皮肤小鼠干细胞的动态突变共发生曲线 使用可自定义的， 单细胞DNA序列平台。这种方法将确定某些突变是否 长期在特定的干细胞种群中选择性地富集和耐受性。 致癌物暴露后功能正常组织的时间。使用的方法 研究很容易适应筛查许多不同的化学暴露，并且具有潜力 检测具有共享干细胞的类似上皮组织系统中癌症的最早迹象 肺和肠道等人群通常会暴露于长期环境 和化学侮辱 - 肿瘤是证据并确定明显的致癌物暴露 细胞中的特征。