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: 10038763
• 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/10038763
• 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; Epithelium; 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; 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.

摘要 早期检测方法的发展是减少癌症增长的基础。 负担基因突变的细胞积累被认为是肿瘤发生的基础 然而，在发展的最早阶段， 肿瘤发生和某些细胞群是否可能更倾向于获得初始的 驱动突变。干细胞是长寿命的细胞，其存在于组织中，并作为 再生池，积极维持正常的稳态，并能修复损伤后的组织。 越来越多的证据表明，干细胞也可以作为起源细胞， 在某些组织中的肿瘤发生，并产生突变细胞的克隆扩增， 随着时间的推移，更容易受到进一步的基因损伤。由于解决不断演变的 突变负担的干细胞在人类个体的组织，这项研究将利用小鼠背 皮肤，一种具有良好表征和独特干细胞的高度信息化再生模型系统 人口。小鼠皮肤特异性干细胞的动态突变共现谱 将使用可定制的， 单细胞DNA测序平台。这种方法将确定某些突变是否 在特定的干细胞群体中， 的时间在功能正常的组织致癌物暴露后。这种方法所使用的 这项研究可以很容易地适用于筛查许多不同的化学品暴露，并且具有潜力 在具有共享干细胞的相似上皮组织系统中检测癌症的最早迹象 肺和肠等人群-这些人群经常暴露于长期的环境中， 和化学损伤-在肿瘤明显并确定明显的致癌物暴露之前 细胞中的信号