Abstract 4178: Lysosomal Storage Dysfunction As a Risk Factor in Pancreatic Cancer

Background: Lysosome is closely linked to autophagy activity which has an important role in pancreatic adenocarcinoma (PDAC). We investigated whether lysosome storage dysfunction (LSD) contributes to PDAC development. Materials and Methods: Comparison of germline putative pathogenic variants (PPV) in genes involved in lysosome functions was performed between PDAC patients (N=418) and healthy controls (N=745) using next generation sequencing. Using mouse pancreas organoid, consequences of GALC downregulation in PDAC development was evaluated. Transcriptome data analysis of human PDAC organoid according to PPV status was followed. Results: PPV in LSD related genes were enriched in PDAC patients compared to healthy controls (Log2OR = 1.65, P = 3.08 × 10−3). For limited stage PDAC patients, PPV carriers were diagnosed with PDAC in younger age compared to non-carriers (mean age 61.5 vs. 65.1 years, p=0.038). In mouse pancreas organoid, Ki-67 index significantly increased as GALC was downregulated. Altered autophagy activity with increased autophagy flux following GALC dysfunction was observed in both human cancer cell line and mouse organoid. mTOR downregulation was noted in mouse pancreas organoid. RNA sequencing analysis of human PDAC organoid revealed metabolism alteration related to LSD. Conclusion: Genetically defined lysosome dysfunction is frequently observed in young age onset PDACs. Lysosome dysfunction might contribute to PDAC development via altered metabolism and autophagy activity. Key words: lysosomal storage disease (LSD), germline, pancreatic ductal adenocarcinoma (PDAC) Citation Format: Hyemin Kim, Youngil Koh, Joo Kyung Park. Lysosomal storage dysfunction as a risk factor in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4178.