Targeting the Metabolic Rewiring in Pancreatic Cancer and Its Tumor Microenvironment

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is characterized by its unique metabolic properties that are established both in a cell-intrinsic and -extrinsic manner, dictated by oncogenic KRAS signaling and shaped in close interaction with the host cells in the tumor microenvironment. Understanding these properties and the underlying mechanisms may reveal novel vulnerabilities that can be therapeutically targeted to improve the patient outcomes and overcome treatment resistance. This review summarizes the mechanisms by which PDAC cells utilize limited nutrients to maximize their growth and obtain nutrients from inside and outside the cells to thrive in a nutrient-scarce microenvironment, with a particular focus on the roles of autophagy in the pathogenesis of PDAC. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with only a few effective therapeutic options. A characteristic feature of PDAC is its unique tumor microenvironment (TME), termed desmoplasia, which shows extensive fibrosis and extracellular matrix deposition, generating highly hypoxic and nutrient-deprived conditions within the tumor. To thrive in this harsh TME, PDAC undergoes extensive metabolic rewiring that includes the altered use of glucose and glutamine, constitutive activation of autophagy-lysosomal pathways, and nutrient acquisition from host cells in the TME. Notably, these properties support PDAC metabolism and mediate therapeutic resistance, including immune suppression. A deeper understanding of the unique metabolic properties of PDAC and its TME may aid in the development of novel therapeutic strategies against this deadly disease.