Author:
Koh Youngil,Kim Hyemin,Song Seulki,Choi Young Hoon,Joo So Young,Kim Hyung Rae,Moon Byul,Byun Jamin,Hong Junshik,Shin Dong-Yeop,Park Solip,Lee Kwang Hyuck,Lee Kyu Taek,Lee Jong Kyun,Park Daechan,Jang Jin-Young,Lee Hyunsook,Kim Jung-Ae,Yoon Sung-Soo,Park Joo Kyung
Abstract
ABSTRACTLysosome 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, P=3.08×10−3). 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.
Publisher
Cold Spring Harbor Laboratory