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不断增长的癌症的基础 负担。基因突变的细胞积累被认为是肿瘤的基础 然而，关于发展的最早阶段，人们基本上缺乏了解 肿瘤发生和某些细胞群体是否更容易获得最初的 驱动突变。干细胞是驻留在组织中的长寿细胞，是一种 积极维持正常动态平衡并能在受伤后修复组织的再生池。 越来越多的证据表明，干细胞也可能是 在某些组织中发生肿瘤并产生突变细胞的克隆性扩张，这可能是 随着时间的推移，更容易受到进一步的基因侮辱。因为要解决不断演变的 干细胞在人类个体组织中的突变负荷，本研究将利用小鼠背部 皮肤，一个具有良好特征和独特干细胞的高度信息量的再生模型系统 人口。小鼠特定皮肤干细胞的动态突变共生图谱 在接触已知致癌物后，将使用可定制的、 单细胞DNA测序平台。这一方法将确定某些突变是否 在特定的干细胞群体中长期选择性地丰富和耐受 在致癌物暴露后的功能正常组织中的时间。它所使用的方法 研究可以很容易地适应于筛查多种不同的化学暴露，并具有潜在的 利用共享干细胞在相似的上皮组织系统中检测癌症的最早迹象 肺脏和肠道等经常暴露在长期环境中的种群 和化学侮辱-在肿瘤明显出现之前，并决定不同的致癌物暴露 单元格中的签名。