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.
Lung cancer is the most frequent type of cancer. In the United States, lung cancer accounted for approximately 14% of all cancer diagnoses and 27% of all cancer deaths in 2016. It is the second most diagnosed cancer in both men and women, but it is the most common cause of cancer-related death in men and women. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and adenocarcinoma is the most common type of NSCLC. Progression from pre-malignant lesions to malignant adenocarcinomas is a hallmark of NSCLC pathogenesis. Our proposed investigations will identify and functionally characterize novel molecular mechanisms that control the transition from premalignant lung lesions to malignant adenocarcinomas. New information that will be obtained from our studies has the potential to directly impact the future development of novel therapeutic interventions to prevent the progression to lung adenocarcinomas.
