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Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer [scRNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE299342 | GEO | 2025/09/26

REPOSITORIES: GEO

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Project description:Many cancers rely on glycolytic metabolism to fuel rapid proliferation. This has spurred interest in designing drugs that target tumor glycolysis such as AZD3965, a small molecule inhibitor of Monocarboxylate Transporter 1 (MCT1) currently undergoing Phase I evaluation for cancer treatment. Since MCT1 mediates proton-linked transport of monocarboxylates such as lactate and pyruvate across the plasma membrane (Halestrap and Meredith, 2004), AZD3965 is thought to block tumor growth through disruption of lactate transport and glycolysis. Here we show that MCT1 inhibition impairs proliferation of glycolytic breast cancer cells that express MCT4 via disruption of pyruvate rather than lactate export. We found that MCT1 expression is elevated in glycolytic breast tumors and cell lines as well as in malignant breast and lung tissues. High MCT1 expression predicts poor prognosis in breast and lung cancer patients. Stable knockdown and AZD3965-mediated inhibition of MCT1 promote oxidative metabolism. Acute inhibition of MCT1 reduces pyruvate export rate but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that also express MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest that MCT1 expression is elevated in glycolytic cancers to promote pyruvate export, which when inhibited enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors that further supports their use as anti-cancer therapeutics. Since MCT1 levels are elevated in glycolytic and malignant breast tumors, we hypothesized that MCT1 may contribute to the Warburg effect metabolic phenotype. To test this hypothesis, we generated whole genome microarray data from breast cancer cell lines either a) expressing a short hairpin (sh)RNA-mediated stable knockdown of MCT1; or b) treated for 24 hours with an MCT1 inhibitor (AZD3965). Scramble shRNA or DMSO were used as controls, and all conditions were analzed in triplicate. The cell lines used â HS578T, SUM149PT, and SUM159PT â are among the most glycolytic in a panel of 31 breast cancer cell lines.

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Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer [scRNA-seq]

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