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

致癌的K-RAS通过提高细胞内的活性氧水平来触发细胞衰老。K-RAS- 表达细胞需要绕过癌基因诱导的衰老(OIS)屏障才能进入更高级别 充满了恶意性。非小细胞肺癌(NSCLC)是最常见的肺癌和 腺癌是最常见的非小细胞肺癌类型。K-RAS突变代表了最常见的分子 肺腺癌的变化。从癌前病变到恶性腺癌的进展是一种 是非小细胞肺癌发病机制的标志。我们提议的调查将直接解决挑衅行为 问题#1通过识别和功能表征控制细胞周期的新的分子机制 从癌前病变向腺癌的转变及其抑制有可能预防 非小细胞肺癌发展。 中心假设：我们提出了小窝蛋白-1控制肺上皮细胞命运的新范式 细胞对致癌RAS的反应。我们认为致癌的K-RAS可诱导癌前病变的衰老 小窝蛋白-1介导的促氧化信号及小窝蛋白-1下调对肺损伤的影响 表达是绕过OIS并推动恶性腺癌进展所必需的。 这一假设将通过追求三个具体目标来检验： 目的1：研究小窝蛋白-1如何促进K-RAS致癌细胞衰老。假设： 癌基因K-RAS通过mTOR激活促进小窝蛋白-1对MTH1功能的抑制，从而导致 肺上皮细胞嘌呤氧化增强、持续DNA损伤反应和细胞衰老 细胞。 目的2：确定表达K-RAS癌基因的细胞如何绕过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基因的表达以逃避OIS。 目的3：确定小窝蛋白-1缺失是否促进了小鼠腺癌的进展 癌基因诱导的肺癌模型。假设：小窝蛋白-1介导的OIS是一种肿瘤抑制因子 机制：基因消融小窝蛋白-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。 这些研究提出了以K-RAS依赖的信号为靶点绕过OIS的新概念 通过下调小窝蛋白-1的表达，这将在本提案中确定，是一种替代和 比以K-RAS本身为靶点更好的治疗选择：它将允许选择性地抑制促肿瘤形成的K-RAS RAS信号转导，同时挽救促衰老的K-RAS通路。这一新信息有可能直接 影响新的治疗干预措施的发展，以防止进展为肺 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.