Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE241236 | GEO | 2025/09/26
REPOSITORIES: GEO
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Project description:<p>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.</p>
2025-09-29 | MTBLS8430 | MetaboLights
Project description: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.
2025-09-26 | GSE299342 | GEO
Project description:Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer
| PRJNA1006765 | ENA
Project description:Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer [scRNA-seq]
| PRJNA1273944 | ENA
Project description:Diets characterized by increased blood levels of ketone bodies can protect the brain against a variety of acute and chronic neurological diseases. Moreover, ketone bodies are neuroprotective in many in vitro models of neurological injury. The underlying mechanisms remain unknown however. Recently, we have shown that ketone bodies do not only decrease neuronal injury and death but also protect long-term potentiation in acute hippocampal slices exposed to oxidative stress in the form of exogenous hydrogen peroxide. Elucidating the mechanisms behind the effects of ketone bodies on neuronal survival and function will undoubtedly lead to the development of novel neuroprotective treatments. Our aim is to determine acute changes in gene expression of CA1 pyramidal neurons exposed to various duration of the ketone bodies acetoacetate and beta-hydroxybutyrate. CA1 hippocampal pyramidal neurons exposed to oxidative stress do not display any long-term potention following burst stimulation of Schaffer collaterals. Incubation with the ketone bodies acetoacetate and beta-hydroxybutyrate for at least 20 min prior to hydrogen peroxide application restores long-term potentiation to control levels. We hypothesize that the neuroprotective effects of ketone bodies are mediated by changes in gene expression. Acute hippocampal slices (400 microns in thickness) were obtained from 4 week-old rats and exposed to acetoacetate and beta-hydroxybutyrate (1 mM each) for 1 h and 6 h. A control group was incubated in artificial cerebrospinal fluid only. After treatment, the hippocampal slices were used immediately for RNA isolation. Isolated RNA was sent for analysis. Each sample sent for analysis included tissue from 7 separate animals. Hybridization to an Affymetrix array is being performed 3 times for each experimental condition.
2008-06-15 | E-GEOD-7323 | biostudies-arrayexpress
Project description:Diets characterized by increased blood levels of ketone bodies can protect the brain against a variety of acute and chronic neurological diseases. Moreover, ketone bodies are neuroprotective in many in vitro models of neurological injury. The underlying mechanisms remain unknown however. Recently, we have shown that ketone bodies do not only decrease neuronal injury and death but also protect long-term potentiation in acute hippocampal slices exposed to oxidative stress in the form of exogenous hydrogen peroxide. Elucidating the mechanisms behind the effects of ketone bodies on neuronal survival and function will undoubtedly lead to the development of novel neuroprotective treatments. Our aim is to determine acute changes in gene expression of CA1 pyramidal neurons exposed to various duration of the ketone bodies acetoacetate and beta-hydroxybutyrate. CA1 hippocampal pyramidal neurons exposed to oxidative stress do not display any long-term potention following burst stimulation of Schaffer collaterals. Incubation with the ketone bodies acetoacetate and beta-hydroxybutyrate for at least 20 min prior to hydrogen peroxide application restores long-term potentiation to control levels. We hypothesize that the neuroprotective effects of ketone bodies are mediated by changes in gene expression. Acute hippocampal slices (400 microns in thickness) were obtained from 4 week-old rats and exposed to acetoacetate and beta-hydroxybutyrate (1 mM each) for 1 h and 6 h. A control group was incubated in artificial cerebrospinal fluid only. After treatment, the hippocampal slices were used immediately for RNA isolation. Isolated RNA was sent for analysis. Each sample sent for analysis included tissue from 7 separate animals. Hybridization to an Affymetrix array is being performed 3 times for each experimental condition. Keywords: dose response
2007-03-20 | GSE7323 | GEO
Project description:Kentucky assay: C5 ketone (2-pentanone)
| PRJNA1096374 | ENA
Project description:Kentucky assay: C8 ketone (2-octanone)
| PRJNA1095543 | ENA
Project description:Kentucky assay: C6 ketone (2-hexanone)
| PRJNA1095545 | ENA
Project description:Kentucky assay: C7 ketone (2-heptanone)
| PRJNA1095538 | ENA