Autophagy Contributes to Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Tumors

Cells. 2022 Jan 26;11(3):426. doi: 10.3390/cells11030426.

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.

Keywords: autophagy; cancer metabolism; mitochondrial metabolism; pancreatic ductal adenocarcinoma; therapeutic resistance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Autophagy / genetics
  • Carcinoma, Pancreatic Ductal* / metabolism
  • Drug Resistance, Neoplasm
  • Humans
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / metabolism
  • Tumor Microenvironment