Metabolic Pathways as a Novel Landscape in Pancreatic Ductal Adenocarcinoma

Abstract

Metabolism plays a fundamental role in both human physiology and pathology, including pancreatic ductal adenocarcinoma (PDAC) and other tumors. Anabolic and catabolic processes do not only have energetic implications but are tightly associated with other cellular activities, such as DNA duplication, redox reactions, and cell homeostasis. PDAC displays a marked metabolic phenotype and the observed reduction in tumor growth induced by calorie restriction with in vivo models supports the crucial role of metabolism in this cancer type. The aggressiveness of PDAC might, therefore, be reduced by interventions on bioenergetic circuits. In this review, we describe the main metabolic mechanisms involved in PDAC growth and the biological features that may favor its onset and progression within an immunometabolic context. We also discuss the need to bridge the gap between basic research and clinical practice in order to offer alternative therapeutic approaches for PDAC patients in the more immediate future.

Metabolic signatures in pancreatic ductal adenocarcinoma: diagnostic and therapeutic implications

“…[29][30][31][32] This metabolic shift, evident from an increase in glucose transporter 1 (GLUT1), indicates that KRAS mutations instigate metabolic reprogramming in early PDAC stages. [33,34] Kras G12D alters the metabolism of PDAC by means of the mitogen-activated protein kinase (MAPK) and myelocytomatosis oncogene (MYC) pathways. [35][36][37] The constitutive MAPK signaling redirects glucose intermediates to hexosamine biosynthesis, whereas the pentose phosphate pathway (PPP) enhances protein glycosylation and nucleotide synthesis.…”

Re-Shaping the Pancreatic Cancer Tumor Microenvironment: A New Role for the Metastasis Suppressor NDRG1

“…In contrast to normal cells, which produce the majority of their energy through mitochondrial oxidative phosphorylation, cancer cells favor aerobic glycolysis, known as the Warburg effect [110], as it supports more biomass production (Figure 4). Although this is a less efficient method of energy production, glycolytic cells produce key metabolites (i.e., pyruvate, lactate), amino acids (i.e., glutamine, alanine), and lipids to enhance proliferation, survival, and invasion [111,112]. In normal cells, pyruvate molecules produced by glycolysis are converted to acetyl CoA for entry into the tricarboxylic acid (TCA) cycle [113].…”