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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.

项目总结/文摘