Tobacco is the leading cause of lung cancer, and is associated with both increased mutation occurrence and dramatic alterations in lung tissue structure and function. Furthermore, about 15% of lung cancers in the U.S. are not associated with smoking, and primarily occur in old age, which is also associated with substantial disruptions in lung structure and function. We do not understand how these changes in lung tissue landscapes impact lung cancer development. A history of smoking is prevalent among veterans, many of whom are reaching older ages, together contributing to substantially higher lung cancer incidence among veterans. This proposal will provide fundamental insight to address several big questions, which have clear implications for early detection and the design of both prevention and treatment strategies for lung cancers: Why are lung cancers more common in smokers, and highly associated with old age for non-smokers, and why are particular oncogenic mutations much more common in smoking related cancers than in aging-associated lung cancers, and vice versus? We know almost nothing about how conditions like smoking or aging alter the lung tissue adaptive landscape, altering selection for different oncogenic events. Using mouse models, we will explore how the different contexts of aging and smoking differentially impact the lung microenvironment and thus select for distinct oncogenic events, and explore the underlying molecular mechanism. These studies could also suggest candidate biomarkers (such as oncogenic clonal expansions or tissue changes) which could be used as indicators of risk for subsequent cancer development. Can interventions that lessen the impacts of aging and smoking on lung microenvironments decrease oncogenic adaptation, and thus decrease the incidence of lung cancers? Using pharmacological and transgenic methods in mice and biopsies from an iloprost lung cancer chemoprevention clinical trial, we will explore anti-inflammatory interventions that might restore the lung landscape (even if partially), thus limiting oncogenic adaptations. While smoking-induced inflammation has been described as a promoter of lung cancer development, it is thought to do so by enhancing pro-cancer phenotypes. We instead propose that smoking exposure (and aging) lead to reductions in the fitness of lung progenitor cell populations (primarily by altering their microenvironment), which leads to increased selection for adaptive mutations. Understanding how modulating inflammation and other microenvironmental alterations can impact oncogenic selection could help guide prevention strategies in humans. While the predominant paradigm largely considers the role of old age in cancer to reflect the time required for oncogenic mutation accumulation, and the role for smoking to be through induction of oncogenic mutations, these studies could indicate that microenvironmental alterations induced by aging and smoking exert substantial influences on oncogene...