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Abstract The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) is only 10%. PDAC is projected to soon become the second leading cause of cancer death. Tobacco is one of the main risk factors for PDAC. Incidence of PDAC increases 2-fold among tobacco users, and 20-35% of PDAC cases are attributed to smoking. However, the specific pathways activated by tobacco carcinogens remain elusive. This research project addresses the impact of carcinogens in pancreatic cancer etiology. We hypothesize that carcinogens in tobacco increase reactive oxygen species (ROS), which elevates the Nrf2 redox pathway to facilitate PDAC initiation and progression. Specifically, we focus on two major subclasses of carcinogens: the heavy metal cadmium (Cd) and the polycyclic aromatic hydrocarbon (PAH) benzo (a) pyrene (BaP). Using mouse pancreatic ductal organoid cultures, we found that acute carcinogen exposure increases Nrf2 activity, which is sustained after "intermediate" exposure (5 passages). Intriguingly, chronic exposure (10 passages) downregulates Nrf2 activity, which has been shown to be associated with acquired metastatic potential. Furthermore, we found an upregulation in NFkB and EGFR signaling after intermediate exposure, which are involved in microenvironment remodeling and increased proliferative potential. Overall, we demonstrate that acute carcinogen exposure elevates ROS levels and activates the Nrf2 pathway, whereas prolonged exposure upregulates NFkB and EGFR pathways. Furthermore, we have established a novel carcinogenesis model using 3D organoid culture to recapitulate each step in pancreatic tumorigenesis. Collectively, this project contributes to our understanding of tobacco-related PDAC pathogenesis. Citation Format: Xiaoxue Lin, McKenna Stamp, Alexandra Fowler, Chelsea Bottomley, Shira Okhovat, Kristina Peck, Dannielle Engle. Tobacco carcinogen impacts redox pathway to facilitate pancreatic ductal adenocarcinoma (PDAC) initiation and progression 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 1466.
Lin et al. (Fri,) studied this question.