Journal
JOURNAL OF GASTROENTEROLOGY
Volume 57, Issue 9, Pages 603-618Publisher
SPRINGER JAPAN KK
DOI: 10.1007/s00535-022-01889-1
Keywords
PDAC; Autophagy; Lysosome; Host autophagy; Anti-tumor immunity
Categories
Funding
- Yasuda Medical Foundation
- MSD Life Science Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Princess Takamatsu Cancer Research Fund
- Life Science Foundation of Japan
- JSPS KAKENHI [21K20828, 22H02898, 22H03053]
- Tokyo Society of Medical Sciences
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [21K20828] Funding Source: KAKEN
Ask authors/readers for more resources
Autophagy plays an important role in pancreatic ductal adenocarcinoma (PDAC). In PDAC, autophagy is constitutively active and enables the tumor to survive and thrive in a nutrient-scarce environment. Autophagy promotes PDAC progression through various mechanisms, including metabolic support, resistance to therapy, and immune evasion. Host autophagy also contributes to PDAC progression. There are ongoing clinical trials targeting the autophagy-lysosome pathway in PDAC.
Macroautophagy (hereafter autophagy) is a catabolic process through which cytosolic components are captured in the autophagosome and degraded in the lysosome. Autophagy plays two major roles: nutrient recycling under starvation or stress conditions and maintenance of cellular homeostasis by removing the damaged organelles or protein aggregates. In established cancer cells, autophagy-mediated nutrient recycling promotes tumor progression, whereas in normal/premalignant cells, autophagy suppresses tumor initiation by eliminating the oncogenic/harmful molecules. Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is refractory to most currently available treatment modalities, including immune checkpoint blockade and molecular-targeted therapy. One prominent feature of PDAC is its constitutively active and elevated autophagy-lysosome function, which enables PDAC to thrive in its nutrient-scarce tumor microenvironment. In addition to metabolic support, autophagy promotes PDAC progression in a metabolism-independent manner by conferring resistance to therapeutic treatment or facilitating immune evasion. Besides to cell-autonomous autophagy in cancer cells, host autophagy (autophagy in non-cancer cells) supports PDAC progression, further highlighting autophagy as a promising therapeutic target in PDAC. Based on a growing list of compelling preclinical evidence, there are numerous ongoing clinical trials targeting the autophagy-lysosome pathway in PDAC. Given the multifaceted and context-dependent roles of autophagy in both cancer cells and normal host cells, a deeper understanding of the mechanisms underlying the tumor-promoting roles of autophagy as well as of the consequences of autophagy inhibition is necessary for the development of autophagy inhibition-based therapies against PDAC.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available