Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer [scRNA-seq]
Tumor-initiating cells (TICs) tend to reside in poorly vascularized regions of tumors and are subjected to nutrient stress. How TICs activate metabolic plasticity for adapting to periods of low nutrient availability, especially during glucose-limiting conditions, has remained unclarified. Here, we discover that lung TICs can induce a metabolic switch from glucose towards ketone utilization specifically during glucose deprivation, whereas bulk, non-TIC cells are unable to do so. Through ex vivo supplementation of ketones or keeping mice on prolonged ketogenic diet, we determine the functional importance of ketones in maintaining the growth and tumor-initiating property of lung TICs. Metabolomics, genomics and metabolic flux tracing studies reveal that ketones feed into ketolysis, fatty acid synthesis and de novo lipogenesis pathways. Surprisingly, ketogenic diet programs the metabolic addiction of TICs towards ketolysis, and this paradoxically induces their therapeutic sensitivity towards the inhibition of the monocarboxylate transporter, MCT1, which imports ketones into cells. Additionally, pharmacological inhibition of fatty acid synthase (FASN) also exerts a more pronounced anti-tumorigenic response in the context of a ketogenic diet. MCT1 function is regulated by the chaperone protein, CD147, and its loss is sufficient to ablate lung TICs under glucose-limiting conditions in vitro and in vivo. Our data reveal a metabolic switch that lung TICs adopt to overcome nutrient stress, and provide the mechanistic bases for how diet manipulation can alter the course of cancer progression or enhance the efficacy of targeted therapy in a context-dependent manner. Overall design: Tumor-initiating cells xenografts harvested from either mice fed with standard chow or ketogenic diet