Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with a 5-year survival rate of only 9%, despite ongoing efforts to improve treatment. This dismal prognosis is due to the difficulty of early stage diagnosis, drug resistance, and likelihood of metastasis development. It is therefore of great importance to identify appropriate therapeutic targets and gain a greater understanding of PDAC biology. Autophagy is a membrane-mediated degradation and recycling mechanism, which is crucial for cell homeostasis. There is evidence for both a tumor-suppressive and a tumor-promoting role of autophagy in cancer, and this is likely context dependent. Within PDAC, a large body of evidence points towards autophagy being required for tumor survival and metabolism. In this review, we describe the recent advances in the understanding of the role and regulation of autophagy in PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all diagnosed pancreatic cancers [1]and is listed as the seventh leading cause of cancer-related death in the world
The section of this review summarizes the recent advances in the understanding of how autophagy is regulated in PDAC, by discussing the new regulators recently uncovered and, where possible, explaining how they may function in autophagy regulation
For PDAC, the majority of studies indicate in metastatic tumors a pro-tumor survival role for autophagy, achieved largely by the contribution of energy and intermediates such as alanine
Summary
Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all diagnosed pancreatic cancers [1]. There is an unmet need for developing new therapies, which may include immunotherapy, targeted therapy or stroma-directed therapy The development of such novel treatments requires an improved understanding of the molecular pathways involved in carcinogenesis and tumor progression, in which autophagy is thought to play a role. There is increasing evidence that lysosomes are important in regulating the autophagic process, both through protein–protein interactions [8], and transcriptionally for example via TFEB [9] As autophagy is such an important cellular process, it is controlled at multiple levels by a large number of signaling platforms located at specific membrane locations, such as the mitochondria and the nucleus [5]. The evidence for the protective and tumorigenic role of autophagy in PDAC tumorigenesis will be summarized, followed by a description of recent advances in the understanding of how autophagy is regulated in PDAC
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