Abstract 4292: Unraveling the interplay of aging, smoking, and mutation-driven clonal expansions in lung cancer evolution: A multifaceted approach

Abstract Despite the well-established link between tobacco use and lung cancer, military personnel face additional risks due to heightened smoking rates and exposure to various environmental contaminants. Aging further amplifies susceptibility to lung cancer, contributing to elevated incidence rates among Veterans compared to non-Veterans. Our studies aim to elucidate the intricate relationship between aging, smoking, and mutation-driven clonal expansions in lung tissue, examining their impact on lung function and cancer evolution. Using cell culture and mouse models, we introduce mutations identified in human lung tissue into airway epithelial cells. Using CRISPR, base editing, and genetically engineered mouse models, we assess the effects on barrier function, cell differentiation, and gene expression. Ultimately, we are investigating the interaction between induced mutations, aging, and smoking, exploring how mutation-driven clonal expansions contribute to lung dysfunction and pre-malignant phenotypes, potentially forming a feedforward loop. This research addresses critical gaps in understanding the complex interplay of aging, smoking, and mutation-driven clonal expansions in lung cancer evolution. Findings have the potential to unveil novel insights into the development of lung dysfunction and malignancy, paving the way for safe and accessible interventions to reduce cancer risk and enhance lung health. Citation Format: Amy N. Briggs, James DeGregori. Unraveling the interplay of aging, smoking, and mutation-driven clonal expansions in lung cancer evolution: A multifaceted approach abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4292.