(548e) A Transient Metabolic State in Melanoma Persister Cells Mediated By Chemotherapeutic Treatments

Conventional cancer therapies are mostly designed to target rapidly proliferating tumor cells. However, recent studies have revealed a small subpopulation of phenotypic variants within the cancer cell population that exhibit increased tolerance to cancer therapeutics (Figure 1A).^1,2 These drug-tolerant cells (also called persisters) employ non-mutational mechanisms to undergo a state of dormancy (Figure 1B). Although cancer persisters are thought to be induced by various stochastic or deterministic factors, a clear understanding behind the phenotypic switch to and from the persistence state is lacking. Despite this knowledge gap, recent studies suggest persisters have unique cellular metabolism.² Employing untargeted metabolomics in our preliminary studies (Figure 1C), we found that Krebs-cycle-substrate levels were significantly downregulated in persister cells compared to those in the cancer bulk population. Cancer cells are known to prefer aerobic glycolysis over oxidative phosphorylation for ATP generation, a phenomenon called the Warburg effect.³ Tumor cells mainly achieve this by reducing the influx into the TCA cycle via tight enzymatic regulations in order to divert glycolytic intermediates into anabolic pathways, essential for cell proliferation. However, due to their slow-proliferating state, we hypothesize persisters may potentially prefer oxidative phosphorylation over aerobic glycolysis to maintain their cellular energy level. This metabolic rewiring may explain the observed reduction in Krebs-cycle-substrate levels in persisters, as these cells might efficiently consume and deplete these substrates. We verified this hypothesis in our study with the use of phenotype microarrays and a tetrazolium-based dye that can measure electron transport chain (ETC) activities (Figure 1D). Furthermore, by assessing the consumption rates of Krebs-cycle substrates in the progenies of persister cells, we showed that the observed metabolic alteration is transient (Figure 1D). We also verified that inhibiting ETC activity in melanoma cells can lead to reduction in persisters derived from various chemotherapeutic agents, verifying that metabolism represents a rich source of anti-persister strategies in melanoma.

References:

1. Sharma, S. V. et al. A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations. Cell 141, 69–80 (2010).
2. Hangauer, M. J. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551, 247–250 (2017).
3. Liberti, M. V. & Locasale, J. W. The Warburg Effect: How Does it Benefit Cancer Cells? Trends in Biochemical Sciences vol. 41 211–218 (2016).