Mechanisms that control the progression from premalignant lesions to adenocarcinomas in the lung

控制肺癌前病变进展为腺癌的机制

基本信息

批准号：
9459856
负责人：
FERRUCCIO GALBIATI
金额：
$ 31.25万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9459856
关键词：
A549 Ablation Address Adenocarcinoma Binding Binding Proteins Biochemical Bypass CAV1 gene Cancer Etiology Cancer Patient Cell Aging Cells Cessation of life Collection DNA Damage Data Development Down-Regulation Epithelial Cells Experimental Designs FRAP1 gene Future Gene Expression Genes Genetic Genetic Screening Growth Guanine Nucleotides Histologic Homologous Gene Human In Vitro Investigation KRAS2 gene Knockout Mice Lesion Libraries Link Lung Lung Adenocarcinoma Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Molecular Mus Mutation Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Oxidative Stress Oxides Pathogenesis Pathway interactions Pharmacology Premalignant Publishing Purines Reactive Oxygen Species Scaffolding Protein Signal Transduction Signaling Molecule Sirolimus Soft Agar Assay Testing Therapeutic Tumor Suppressor Proteins United States Woman cancer cell cancer diagnosis cancer type caveolin 1 genetic approach in vivo insight men migration mouse model novel novel therapeutic intervention overexpression oxidation preclinical study premature pressure prevent protein K response senescence small hairpin RNA subcutaneous tumor tumor xenograft tumorigenic

项目摘要

Oncogenic K-Ras triggers cellular senescence by raising intracellular levels of reactive oxygen species. K-Ras- expressing cells need to bypass the oncogene-induced senescence (OIS) barrier to progress to higher grades of malignancy. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and adenocarcinoma is the most common type of NSCLC. K-Ras mutations represent the most common molecular change in lung adenocarcinomas. Progression from pre-malignant lesions to malignant adenocarcinomas is a hallmark of NSCLC pathogenesis. Our proposed investigations will directly address Provocative Question #1 by identifying and functionally characterizing novel molecular mechanisms that control the transition from premalignant lung lesions to adenocarcinomas and whose inhibition has the potential to prevent NSCLC development. Central hypothesis: we advance the novel paradigm that caveolin-1 controls the fate of lung epithelial cells in response to oncogenic Ras. We propose that oncogenic K-Ras induces senescence in premalignant lung lesions through a caveolin-1-mediated pro-oxidative signaling and that downregulation of caveolin-1 expression is necessary to bypass OIS and drive the progression to malignant adenocarcinomas. This hypothesis will be tested by pursuing three specific aims: Aim 1: Determine how caveolin-1 promotes oncogenic K-Ras-induced cellular senescence. Hypothesis: inhibition of MTH1 function by caveolin-1 is promoted by oncogenic K-Ras via mTOR activation, which leads to enhanced purine oxidation, sustained DNA damage response (DDR) and cellular senescence in lung epithelial cells. Aim 2: Identify how oncogenic K-Ras-expressing cells bypass OIS. Hypothesis: a selective pressure exists in oncogenic K-Ras-expressing cells that downregulates caveolin-1 gene expression to elude OIS. Aim 3: Determine if a lack of caveolin-1 promotes the progression to adenocarcinomas in mouse models of oncogene-induced lung cancer. Hypothesis: Caveolin-1-mediated OIS is a tumor suppressor mechanism: the genetic ablation of caveolin-1 inhibits the formation of premalignant and senescent-positive lung lesions in favor of malignant and senescent-negative adenocarcinomas. These investigations propose the novel concept that targeting K-Ras-dependent signaling that bypasses OIS through downregulaton of caveolin-1 expression, which will be identified in this proposal, is an alternative and better therapeutic option then targeting K-Ras itself: it will allow the selective inhibition of pro-tumorigenic K- Ras signaling while rescuing pro-senescent K-Ras pathways. This new information has the potential to directly impact the development of novel therapeutic interventions to prevent the progression to lung adenocarcinomas.

致癌 K-Ras 通过提高细胞内活性氧水平来引发细胞衰老。 K-Ras- 表达细胞需要绕过癌基因诱导的衰老（OIS）屏障才能进展到更高级别的恶性肿瘤。非小细胞肺癌（NSCLC）是最常见的肺癌形式，腺癌是最常见的 NSCLC 类型。 K-Ras 突变是最常见的分子突变肺腺癌的变化。从癌前病变进展为恶性腺癌是 NSCLC 发病机制的标志。我们提议的调查将直接解决挑衅性问题问题#1 通过识别和功能表征控制的新分子机制从癌前肺部病变转变为腺癌，其抑制有可能预防非小细胞肺癌的发展。中心假设：我们提出了 Caveolin-1 控制肺上皮细胞命运的新范式细胞对致癌 Ras 的反应。我们提出致癌 K-Ras 会诱导癌前病变的衰老通过 Caveolin-1 介导的促氧化信号传导以及 Caveolin-1 的下调来调节肺部病变表达对于绕过 OIS 并驱动恶性腺癌的进展是必要的。该假设将通过追求三个具体目标来检验：目标 1：确定 Caveolin-1 如何促进致癌 K-Ras 诱导的细胞衰老。假设：致癌 K-Ras 通过 mTOR 激活促进 Caveolin-1 对 MTH1 功能的抑制，从而导致增强嘌呤氧化、持续 DNA 损伤反应 (DDR) 和肺上皮细胞衰老细胞。目标 2：确定表达致癌 K-Ras 的细胞如何绕过 OIS。假设：存在选择压力在致癌 K-Ras 表达细胞中，下调 Caveolin-1 基因表达以逃避 OIS。目标 3：确定 Caveolin-1 的缺乏是否会促进小鼠进展为腺癌癌基因诱导的肺癌模型。假设：Caveolin-1 介导的 OIS 是一种肿瘤抑制因子机制：caveolin-1的基因消除抑制癌前和衰老阳性细胞的形成肺部病变有利于恶性和衰老阴性腺癌。这些研究提出了一个新概念，即针对绕过 OIS 的 K-Ras 依赖性信号传导通过下调 Caveolin-1 表达（将在本提案中确定）是一种替代方案比靶向 K-Ras 本身更好的治疗选择：它将选择性抑制促肿瘤 K- Ras 信号转导同时拯救促衰老的 K-Ras 通路。这些新信息有可能直接影响新型治疗干预措施的发展，以防止进展到肺部腺癌。