A well-established and intriguing function of K-Ras is its ability to promote oncogene-induced senescence (OIS) through the elevation of reactive oxygen species (ROS). Since senescent cells can not proliferate, cellular senescence is a powerful tumor suppressor mechanism. In vivo data suggest that OIS is a barrier that prevents oncogenic K-Ras-transformed cells to proliferate and progress to higher grades of malignancy. The identification of the molecular signaling through which cells expressing oncogenic K-Ras undergo OIS is fundamental for gaining insights into how premalignant lesions restrain from progressing to cancer. PTRF is an essential component in the biogenesis and function of caveolae, flask-shaped invaginations of the plasma membrane involved in signal transduction. Our published data show that PTRF promotes oxidative stress- induced premature senescence. Central hypothesis: we advance the novel paradigm that PTRF-mediated pro-oxidative signaling promotes oncogenic K-Ras-induced senescence in premalignant lung lesions and prevents the progression to malignant adenocarcinomas. This hypothesis will be tested by pursuing two specific aims: Aim 1: Determine if PTRF promotes oncogenic K-Ras-induced cellular senescence. Hypothesis: activation of NOX2 by PTRF in caveolae is promoted by oncogenic K-Ras and leads to ROS-dependent cellular senescence. Aim 2: Determine if a lack of PTRF promotes tumorigenesis in mouse models of K-Ras-induced lung cancer. Hypothesis: PTRF-mediated OIS is a tumor suppressor mechanism: the genetic ablation of PTRF inhibits the formation of premalignant and senescent-positive lung lesions in favor of malignant and senescent- negative adenocarcinomas. These investigations will provide novel insights into the molecular mechanisms that regulate oncogene-induced senescence at the cellular and animal levels. Our studies also propose the concept that therapeutic strategies aimed at boosting PTRF-mediated signaling may represent novel and better therapeutic options than those centered on inhibition of K-Ras, which have failed in the past. In fact, they would allow the enhancement of pro-senescent and anti-tumorigenic K-Ras-dependent pathways and therefore the inhibition of the progression to lung adenocarcinoma.