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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：
9305499
负责人：
FERRUCCIO GALBIATI
金额：
$ 31.03万
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/9305499
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 Tumorigenicity 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通过提高细胞内活性氧水平触发细胞衰老。k - - - - - - -