Genetic dissection of oncogenic RAS-driven tumor initiation in vivo

体内致癌 RAS 驱动的肿瘤发生的基因剖析

• 批准号: 10415753
• 负责人: CHRISTOPHER M COUNTER
• 金额: $ 49.82万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415753
• 关键词: Address; Alleles; Bacteria; Biological Assay; Biological Models; Biology; Cancer Biology; Cancer Patient; Carcinogen exposure; Cells; Clinical; Data; Disease; Dissection; Early Diagnosis; Engineering; Event; Family; Foundations; Frequencies; Genes; Genetic; Genetic Induction; Genetically Engineered Mouse; Goals; Human; Individual; Induced Mutation; Investigation; KRAS oncogenesis; KRAS2 gene; Lesion; Lung; Malignant Neoplasms; Methods; Modeling; Monitor; Mus; Mutagenesis; Mutate; Mutation; Nature; Normal Cell; Oncogenes; Oncogenic; Pathologic Mutagenesis; Pattern; Positioning Attribute; Prevention; Process; Protein Isoforms; Proteins; Publishing; RAS genes; Refractory; Reporting; Severities; Signal Transduction; Tissues; Tumor-Associated Process; Urethane; base; cancer initiation; cancer type; carcinogenesis; cell type; clinically relevant; de novo mutation; in vivo; individual response; innovative technologies; insight; mouse model; mutant; next generation; novel; potential biomarker; prevent; response; single-cell RNA sequencing; therapeutic target; tumor; tumor initiation; tumorigenesis; tumorigenic

PROJECT SUMMARY/ABSTRACT The RAS family comprised of KRAS, NRAS, and HRAS are the most commonly mutated oncogenes in human cancer. Despite there being over 50 possible oncogenic RAS mutations, each cancer type has a specific and often unique subset of these mutations. As RAS mutations typically occur early during tumorigenesis, if not being the initiating mutation, these mutational patterns reflect fundamental biology underlying the process of tumor initiation. Elucidating the mechanisms giving rise to RAS mutation patterns would therefore address a foundational question in cancer biology- how cancer originates. Given this, the most informative approach to interrogate these patterns is to study RAS mutations when they 1) first occur in 2) normal cells in an 3) in vivo setting. Trying to backtrack to catch that one random mutagenic event in one gene from one cell that initiates cancer decades before manifesting as a disease is challenging in humans. There are, however, two murine model systems that allow an initiating RAS mutation to be precisely defined, and hence are amenable to studying RAS mutation patterns. One, carcinogenesis, which is particularly well suited to interrogate how the mutagenic process gives rise to RAS mutation patterns. Two, genetic activation of mutant alleles in a spatially and temporally restricted fashion, which is ideal to study the response of defined Ras mutations in normal cells. We thus propose to capitalize on the individual strengths of these two different models to elucidate the mechanisms by which RAS mutation patterns are laid down in normal cells at the very onset of tumorigenesis in vivo. Specifically, in aim 1 we will determine how tumors arise by a specific Ras mutation by monitoring mutagenesis immediately after carcinogen exposure and thereafter in genetic backgrounds that alter RAS mutation patterns. In aim 2 we will determine the signaling and cellular responses of different normal cells upon genetic induction of different oncogenic Ras mutants. Completion of this proposal will thus elucidate the principles underlying the selection for specific RAS mutations in human cancers, and more broadly, how cancers originate, which has clinical implications for early detection and prevention.

项目摘要/摘要 由KRAS，NRA和HRA组成的RAS家族是人类中最常见的肿瘤基因 癌症。尽管有50多个可能的致癌性RAS突变，但每种癌症类型都有特定的和 这些突变通常是独特的子集。由于RAS突变通常发生在肿瘤发生期间的早期，如果不是 作为引发突变，这些突变模式反映了基本生物学的基础 肿瘤的启动。因此，阐明产生RAS突变模式的机制将解决 癌症生物学中的一个基本问题 - 癌症是如何产生的。鉴于此，最有用的方法 询问这些模式是研究RAS突变时1）首次出现在2）An 3）体内的正常细胞中 环境。试图回溯到一个启动的一个细胞中的一个基因中捕获一个随机的诱变事件 在表现为疾病的几十年癌症在人类中具有挑战性。但是，有两个鼠 允许精确定义启动RAS突变的模型系统，因此可以研究 RAS突变模式。一种，致癌作用，特别适合询问诱变 过程产生RAS突变模式。两个，突变等位基因在空间上的遗传激活和 在时间上受到限制的方式，这是研究正常细胞中定义的RAS突变的响应的理想选择。我们 因此，建议利用这两个不同模型的个体优势来阐明机制 在体内肿瘤发生的过程中，正常细胞中的RAS突变模式在正常细胞中定位。 具体而言，在AIM 1中，我们将通过监测诱变来确定特定的RAS突变如何产生肿瘤 致癌物暴露并在改变RAS突变模式的遗传背景下立即。 在AIM 2中，我们将在遗传诱导后确定不同正常细胞的信号传导和细胞反应 不同的致癌Ras突变体。因此，该提案的完成将阐明 选择人类癌症中特定的RAS突变，更广泛地，癌症如何起源 早期检测和预防的临床意义。