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.

致癌的K-Ras通过增加细胞内的活性氧触发细胞衰老。 k-ras- 表达细胞需要绕过癌基因诱导的衰老（OIS）屏障才能发展到更高等级恶性肿瘤。非小细胞肺癌（NSCLC）是肺癌和腺癌是最常见的NSCLC类型。 K-RAS突变是最常见的分子肺腺癌的变化。从恶性病变到恶性腺癌的发展是一个 NSCLC发病机理的标志。我们拟议的调查将直接解决挑衅性问题1通过识别和功能表征控制的新型分子机制从肺部病变过渡到腺癌，其抑制作用有可能预防 NSCLC开发。中央假设：我们推进了小窝蛋白-1控制肺上皮命运的新型范式细胞响应致癌性Ras。我们建议致癌K-RAS会引起衰老前的衰老通过小窝蛋白1介导的促氧化信号传导的肺部病变，可爱素-1的下调表达对于绕过OI并推动对恶性腺癌的发展是必要的。该假设将通过追求三个具体目标来检验： AIM 1：确定小窝蛋白-1如何促进致癌K-RAS诱导的细胞衰老。假设： Caveolin-1对MTH1功能的抑制是通过MTOR激活来促进的，这导致增强的嘌呤氧化，持续的DNA损伤反应（DDR）和肺上皮中的细胞衰老细胞。 AIM 2：确定致癌K-RAS的细胞如何绕过OI。假设：存在选择性压力在表达K-RAS的致癌细胞中，将小窝蛋白-1基因表达下调至渗透OI。 AIM 3：确定缺乏小窝蛋白-1是否促进了小鼠中腺癌的发展癌基因诱导的肺癌的模型。假设：小窝蛋白1介导的OI是肿瘤抑制剂机制：小窝蛋白-1的遗传消融抑制了前态和衰老阳性的形成肺部病变有利于恶性和衰老阴性腺癌。这些调查提出了一个新的概念，即靶向K-RAS依赖的信号传导绕过OIS 通过Caveolin-1表达的下调，将在本提案中识别出来，是一种替代方案，更好的治疗选择，而不是针对K-RAS本身：它将允许选择性抑制促肿瘤k- RAS发出信号传导，同时挽救了阳性K-RAS途径。这些新信息有可能直接影响新型治疗干预措施的发展，以防止肺发展腺癌。