The role of metabolic adaptation to nutrient stress in pancreatic cancer

Abstract

Pancreatic cancer is the fourth most common cause of cancer-related mortality, with a dismal prognosis that has changed little over the past few decades. Despite extensive efforts in understanding the oncogenetics of this pathology, pancreatic cancer remained largely elusive. One of the main characteristics of pancreatic cancer is the reduced level of oxygen and nutrient perfusion, caused by the new matrix formation, through the activation of stromal cells (desmoplasia). This stromal reaction leads to metabolic adaptations in surviving tumor cells in order to cope with these challenging conditions. The oncogenic signaling driven by KRAS mutation is necessary to fuel pancreatic tumors by activating key metabolic processes, including enhanced glycolysis and glutamine consumption. Here we review our current understanding of the pancreatic cancer metabolism as well as discuss recent work pointing to the importance of various metabolic strategies as well as autophagy and macropinocytosis as critical nutrient supply pathways. The elucidation of these metabolic networks may highlight new opportunities to further develop novel therapeutic strategies.

Keywords: autophagy; macropinocytosis; metabolic rewiring; nutrient stress; pancreatic cancer.

Figure 1. FIGURE 1: Macroautophagy and macropinocytosis as pro-survival mechanisms to sustain cancer cell metabolism in a nutrient limiting environment.

Under nutrient rich conditions, cancer cells take up glucose and amino acids through membrane transporters and they can be used to support glycolysis and tricarboxylic acid (TCA), producing ATP and intermediates for anabolic processes. However, PDAC is completely surrounded by a fibrotic barrier, thus limiting the nutrients' delivery to the tumor cells. For this reason, PDAC cells develop two different lysosomal degrading mechanisms. Macroautophagy is a catabolic degradation of damaged cytoplasmic components (organelles and macromolecules), while macropinocytosis is a catabolic degradation of extracellular components previously internalized by the cell. Both mechanisms can produce amino acids and other nutrients that can fuel cell metabolism and sustain survival and proliferation. α-KG: α-ketoglutarate; AcCoA: acetyl coenzyme A; Asp: Aspartate; G6P: glucose-6-phosphate; GOT1: Glutamic-oxaloacetic transaminase 1; GLS: Glutaminase; GLUD: Glutamate Dehydrogenase; GLUT: Glucose Transporter; HK 1/2: hexokinase 1/2; LDH: lactate dehydrogenase; MCT 1/4: Monocarboxylate transporter 1/4; MDH1: Malate Dehydrogenase 1; ME: Malate dehydrogenase; mTOR: mammalian target of rapamycin; NADPH: nicotinamide adenine dinucleotide phosphate; OAA: oxaloacetate; PEP: Phosphoenolpyruvate; PKM2: Pyruvate kinase isozymes M2; SLC1A5: Solute Carrier Family 1, member 5; TCA: tricarboxylic acid.