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: 10461785
• 负责人: Eve Kandyba
• 金额: $ 9.72万
• 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/10461785
• 关键词: Address; Automobile Driving; Biological Assay; Biological Models; Cancer Burden; Carcinogen exposure; Carcinogens; Cell Compartmentation; Cells; Chemical Agents; Chemical Exposure; Clonal Expansion; DNA Sequence Alteration; DNA sequencing; Development; Dorsal; Early Diagnosis; Epithelial; Exposure to; Foundations; Genetic; Genetic Anticipation; Homeostasis; Individual; Injury; Intestines; Knowledge; Lung; Malignant Neoplasms; Mus; Mutate; Mutation; Normal tissue morphology; Pattern; Population; Skin; System; Time; Tissues; carcinogenicity; environmental chemical; 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增长至关重要 负担。基因突变的细胞积累被认为是肿瘤的基础 然而，人们对发展的最早阶段缺乏了解。 肿瘤发生以及某些细胞群是否更容易获得初始 驱动突变。干细胞是长寿命细胞，存在于组织中并充当 再生池积极维持正常的体内平衡并可以修复受伤后的组织。 越来越多的证据表明，干细胞也可能作为细胞的起源细胞。 某些组织中的肿瘤发生并产生突变细胞的克隆扩增，这可能是 随着时间的推移，更容易受到进一步的基因损伤。由于解决不断变化的问题是不可行的 人类个体组织中干细胞的突变负担，这项研究将利用小鼠背部 皮肤，一个信息丰富的再生模型系统，具有特征明确且独特的干细胞 人口。特定皮肤小鼠干细胞的动态突变共现谱 将利用可定制的、暴露于已知致癌物后确定的人群， 单细胞DNA测序平台。这种方法将确定某些突变是否 长期选择性富集和耐受特定干细胞群的特征 暴露于致癌物后功能正常组织的时间。本次使用的方法 研究可以很容易地应用于筛查许多不同的化学物质暴露，并且具有潜力 检测具有共享干细胞的相似上皮组织系统中癌症的最早迹象 肺部和肠道等经常暴露于长期环境的人群 和化学损伤 - 在肿瘤明显并确定明显的致癌物暴露之前 单元格中的签名。