Lysosome is closely linked to autophagy, which plays a vital role in pancreatic adenocarcinoma (PDAC) tumor biology. This study investigated whether lysosome storage dysfunction (LSD) contributes to PDAC development. Germline putative pathogenic variants (PPVs) in genes involved in lysosome functions were compared between PDAC patients (N=418) and healthy controls (N=845). Furthermore, Galc-knockout mouse pancreas organoids and human PDAC organoids were used to evaluate the consequences of PPV status in PDAC development and establishment. LSD PPVs were enriched in PDAC patients (Log2OR=1.65). PPV carriers diagnosed with PDAC were younger than non-carriers (61.5 vs. 65.3 years, P=0.031). Hampered autophagolysosome activity with increased autophagy flux and elevated Ki-67 index were observed following GALC downregulation. RNA sequencing of human PDAC organoids revealed upregulation of metabolism related to LSD. Genetically defined lysosome dysfunction is frequently observed in young-age onset PDACs. Lysosome dysfunction might contribute to PDAC development via altered metabolism and impaired autophagolysosome activity.

The authors have declared no competing interest.

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (Grant No. NRF-2020R1A2C2102023) (YK) and the Ministry of Health & Welfare, Republic of Korea (Grant No. HI18C1876) (SSY). This study was supported by the Future Medicine 20*30 project of the Samsung Medical Center (Grant No. SMX1230041, SMX1220111) and Samsung Medical Center Research and Development Grant (Grant No. SMO1230661) (JKP).

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This study was conducted under the principles of the Declaration of Helsinki, and the study protocol was approved by the institutional review board (IRB) of SMC and SNUH. All patients and volunteers provided written informed consent, and all specimens were collected according to IRB regulations and approval (IRB No. 2018-12-065, 1705-031-852).

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All data produced in the present study are available upon reasonable request to the authors