The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance

Abstract

Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that is highly refractory to the current standards of care. The difficulty in treating this disease is due to a number of different factors, including altered metabolism. In PDA, the metabolic rewiring favors anabolic reactions which supply the cancer cell with necessary cellular building blocks for unconstrained growth. Furthermore, PDA cells display high levels of basal autophagy and macropinocytosis. KRAS is the driving oncogene in PDA and many of the metabolic changes are downstream of its activation. Together, these unique pathways for nutrient utilization and acquisition result in metabolic plasticity enabling cells to rapidly adapt to nutrient and oxygen fluctuations. This remarkable adaptability has been implicated as a cause of the intense therapeutic resistance. In this review, we discuss metabolic pathways in PDA tumors and highlight how they contribute to the pathogenesis and treatment of the disease.

Keywords: Autophagy; Macropinocytosis; Metabolism; Microenvironment; Pancreatic cancer.

Figure 1.

Representative image of metabolic cross-talk in the PDA microenvironment. Moving further from the vasculature results in the decrease in nutrient content and increase in hypoxia. PDA Cells (green cell, magenta nucleus) in the nutrient devoid and hypoxic areas of the tumor display increased autophagy (represented by blue dots with red outlines) and lactate secretion (curved black arrows). Secreted lactate serves as a fuel source for neighboring PDA cells. Stellate cells (orange cell, purple nucleus) secrete alanine into the microenvironment (orange arrows) which is rapidly consumed by PDA cells. The process of autophagy-dependent alanine secretion is stimulated by PDA cells through release of an unknown factor (straight black arrow). Collagen (blue area) is deposited by activated stellate cells into the TME. Through macropinocytosis (dark green membrane protrusions on tumors cell), cell can uptake extracellular protein as well as components of the ECM (like collagen) as an external fuel source for central carbon metabolism.

Figure 2.

PDA cells have a remarkable ability to adapt to nutrient fluctuations and targeted therapies. For example, PDA cells can rapidly adapt to GLS inhibition (GLSi) through multiple mechanisms of metabolic rewiring. Blocking the conversion of glutamine to glutamate perturbs redox balance in PDA cells by disrupting the initial steps of the non-canonical glutamine pathway that generates NADPH. One means by which PDA overcomes GLSi is by upregulating cellular reactions that generate glutamate bypassing the need for GLS activity (lower red box). Scavenging by macropinocytosis (blue membrane protrusion) and recycling by autophagy (dark blue forming phagophore) of macromolecules through the lysosome (dark blue circle, red dots) can also generate glutamate to fuel PDA metabolism downstream of GLS. Another means of adaptation is by directly upregulating metabolic reactions that restore reducing potential of the cell (upper red box). The plasticity of PDA metabolism allows for adaption at multiple levels making the cells exceptionally resistant to microenvironmental or therapeutic induced changes in nutrients.