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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要 RAS家族由KRAS、NRAS和HRAS组成，是人类最常见的突变癌基因癌症。尽管存在超过 50 种可能的致癌 RAS 突变，但每种癌症类型都有其特定的和通常是这些突变的独特子集。由于 RAS 突变通常发生在肿瘤发生的早期，如果不是的话作为起始突变，这些突变模式反映了该过程背后的基础生物学肿瘤起始。因此，阐明引起 RAS 突变模式的机制将解决癌症生物学的一个基本问题——癌症是如何起源的。鉴于此，最有效的方法是询问这些模式是为了研究 RAS 突变何时 1) 首次出现在 2) 正常细胞中 3) 体内环境。试图回溯以捕获启动的一个细胞的一个基因中的一个随机诱变事件癌症在人类中呈现为一种疾病之前数十年是具有挑战性的。然而，有两种小鼠允许精确定义起始 RAS 突变的模型系统，因此适合研究 RAS 突变模式。一是致癌作用，特别适合探究突变是如何发生的。过程产生 RAS 突变模式。二、突变等位基因在空间和空间上的遗传激活时间限制的时尚，这是研究正常细胞中定义的 Ras 突变的反应的理想选择。我们因此建议利用这两种不同模型的各自优势来阐明其机制 RAS突变模式在体内肿瘤发生一开始就在正常细胞中确定。具体来说，在目标 1 中，我们将通过监测突变来确定特定 Ras 突变如何产生肿瘤在接触致癌物后立即发生，随后在改变 RAS 突变模式的遗传背景中发生。在目标 2 中，我们将确定不同正常细胞在基因诱导后的信号传导和细胞反应不同的致癌Ras突变体。因此，完成本提案将阐明该提案背后的原则。选择人类癌症中特定的 RAS 突变，更广泛地说，研究癌症的起源，这已经对早期发现和预防的临床意义。