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Metabolic plasticity allows cancer cells to thrive under nutrient starvation

Dysregulated metabolism contributes to central characteristics of cancer cells such as sustained proliferation, resistance toward cell death, and epigenetic alterations (1). At the same time, the process of cellular transformation and tumorigenesis creates new metabolic challenges. Cancer cells commonly encounter harsh metabolic conditions such as poorly vascularized tumors or distant tissues, where they are exposed to fluctuating or unfamiliar nutrient environments. Cancer cells navigate these metabolic stresses by selecting for increased metabolic flexibility and resilience. To better understand the underlying processes, Tsai et al. (2) explore in PNAS the adaptations of pancreatic cancer cells to limited nutrient supply, as is characteristic for solid tumors. Research into cancer metabolism initially focused on processes that increase anabolism and growth. Many cancer cells avidly take up glucose and excrete excess glucose-derived carbons as lactate—a phenomenon referred to as aerobic glycolysis or the Warburg effect (3). Cancer cells further take up large quantities of glutamine, a nonessential amino acid that provides a source for both reduced carbon and nitrogen. In proliferating cells, glucose and glutamine constitute major fuels for central carbon metabolism, which supplies energy, reducing equivalents and biosynthetic precursors (1, 3). Although glucose and glutamine are preferred nutrients, cancer cells often compensate for shortage of either glucose or glutamine by increasing utilization of the other nutrient. Metabolism of glucose and glutamine supplies reduced carbons to the tricarboxylic acid (TCA) cycle, which generates electrons for the respiratory chain as well as various biosynthetic precursors. Flexible use of either glucose or glutamine for TCA cycle anaplerosis thus allows cancer cells to sustain these metabolic activities (1, 4). Glutamine further serves as a source of reduced nitrogen, which is required for the biosynthesis of amino acids, nucleotides, and amino sugars. However, when glutamine is limiting, expression of branched chain amino acid transferases enables cancer cells to acquire reduced nitrogen from isoleucine, leucine, and valine (5). The remarkable metabolic flexibility of cancer cells has received increasing attention, but the underlying mechanisms are insufficiently understood. Addressing this problem is imperative, not only for the fundamental understanding of cancer metabolism but also, for its therapeutic exploitation. A case in point is the development of pharmacological inhibitors of glycolysis and glutaminolysis, which have not lived up to expectations. In light of the centrality of glucose and glutamine metabolism, this may have been Fig. 1. Investigating metabolic plasticity in pancreatic cancer cells. Several human PDA cell lines were cultured in starvation media (0.5 mM glucose [gluc]/0.1 mM glutamine [gln]) for several weeks. From the surviving cells, several clonal lines were established. Starvation-adapted clones could proliferate in glucose/ glutamine-deprived media and displayed increased tumor formation in mice. Adapted clones further displayed consistent molecular alterations, including increased mTORC1 activity, glutamine synthesis, and chromatin accessibility. These changes were reversible and gradually lost when starvation-adapted clones were reverted to full media.