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

致癌性K-Ras通过提高细胞内活性氧水平触发细胞衰老。克-拉斯- 表达癌基因的细胞需要绕过癌基因诱导的衰老（OIS）屏障才能进展到更高的级别 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突变代表了最常见的 肺腺癌的变化。从癌前病变进展为恶性腺癌是一个重要的因素。 NSCLC发病机制的标志。我们提议的调查将直接针对挑衅性 问题#1通过识别和功能性表征新的分子机制，控制 从癌前肺病变向腺癌的转变，并且其抑制有可能预防 NSCLC发展。 中心假设：我们提出了新的范式，即小窝蛋白-1控制肺上皮细胞的命运， 细胞对致癌Ras的反应。我们认为致癌K-Ras诱导癌前病变细胞衰老， 通过小窝蛋白-1介导的促氧化信号传导和小窝蛋白-1的下调导致肺损伤 表达是绕过OIS并驱动向恶性腺癌进展所必需的。 将通过追求三个具体目标来检验这一假设： 目的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： 致癌K-Ras通过mTOR激活促进小窝蛋白-1对MTH 1功能的抑制，这导致 肺上皮细胞嘌呤氧化增强、持续DNA损伤反应（DDR）和细胞衰老 细胞 目的2：确定致癌K-Ras表达细胞如何绕过OIS。假设：存在选择性压力 在表达致癌K-Ras的细胞中，下调小窝蛋白-1基因表达以逃避OIS。 目的3：确定缺乏小窝蛋白-1是否促进小鼠腺癌的进展 癌基因诱导的肺癌模型。假设：Caveolin-1介导的OIS是肿瘤抑制因子 机制：基因切除小窝蛋白-1抑制癌前病变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。 这些研究提出了靶向绕过OIS的K-Ras依赖性信号传导的新概念 通过下调小窝蛋白-1的表达，这将在本建议中确定，是一种替代方法， 更好的治疗选择，然后靶向K-Ras本身：它将允许选择性抑制促肿瘤发生的K- Ras信号转导，同时拯救促衰老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开发，以防止进展到肺 腺癌

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.