Abstract
Metabolic reprogramming is a feature of cancers for which recent research has been particularly active, providing numerous insights into the mechanisms involved. It occurs across the entire cancer process, from development to resistance to therapies. Established tumors exhibit dependencies for metabolic pathways, constituting vulnerabilities that can be targeted in the clinic. This knowledge is of particular importance for cancers that are refractory to any therapeutic approach, such as Pancreatic Ductal Adenocarcinoma (PDAC). One of the metabolic pathways dysregulated in PDAC is autophagy, a survival process that feeds the tumor with recycled intracellular components, through both cell-autonomous (in tumor cells) and nonautonomous (from the local and distant environment) mechanisms. Autophagy is elevated in established PDAC tumors, contributing to aberrant proliferation and growth even in a nutrient-poor context. Critical elements link autophagy to PDAC including genetic alterations, mitochondrial metabolism, the tumor microenvironment (TME), and the immune system. Moreover, high autophagic activity in PDAC is markedly related to resistance to current therapies. In this context, combining autophagy inhibition with standard chemotherapy, and/or drugs targeting other vulnerabilities such as metabolic pathways or the immune response, is an ongoing clinical strategy for which there is still much to do through translational and multidisciplinary research.
Highlights
Received: 21 December 2021Pancreatic cancer remains a poor-outcome disease with mortality rates nearly identical to incidence rates
We showed that TP53INP1 is lost in early stages of Pancreatic Ductal Adenocarcinoma (PDAC) development before the acquisition of p53 mutations, and that this loss is associated with oxidative stress promoting oncogenic KRAS-driven tumorigenesis [78–80]
Autophagy in skeletal muscle is a key proteolysis pathway which is activated during PDAC-induced cachexia and sarcopenia, suggesting that it may participate in the feeding of PDAC tumors with amino-acids originating from the sarcopenic muscle [89–92]
Summary
Pancreatic cancer remains a poor-outcome disease with mortality rates nearly identical to incidence rates. Activating oncogenic mutations in KRAS are considered the major genetic initiating event in PDAC carcinogenesis and are present in 92–95% of cases [11,12] They can be present in early premalignant lesions ADM and PanINs [9,13,14]. TP53, CDKN2A, and SMAD4, occur later during disease progression and are frequently observed with different percentages of cases (Figure 1) All these genetic alterations influence tumorigenesis affecting cell growth, cell metabolism, cell proliferation, and protein synthesis, collectively altering cellular homeostasis [15]. PDAC is characterized by an inflammation-induced desmoplastic reaction that results in a dense fibrotic stroma, consisting of abundant extracellular matrix (ECM) and stromal cells in the TME (Figure 1) This TME is very heterogeneous in terms of the variety of stromal cell subtypes, which includes cancer-associated fibroblasts (CAFs), immune cells, stroma-associated pancreatic stellate cells (PSCs), adipocytes, endothelial cells, and neurons. In PDAC, autophagy can prevent cancer initiation at early steps of the disease, and in established tumors, autophagy supports PDAC growing and maintenance by different mechanisms
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
