Rewiring of cortical glucose metabolism fuels human brain cancer growth
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PROVIDER: PRJNA1272587 | ENA |
REPOSITORIES: ENA
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Project description:The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to drive aggressive growth remains elusive. Here, we infused 13C-labeled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumor vs. cortex. Through the first direct and comprehensive measurements of carbon and nitrogen labeling in both cortex and glioma tissues, we uncover profound metabolic transformations. In human cortex, glucose carbons fuel essential physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters GBM metabolism, slows tumor growth, and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumors exploit glucose to suppress normal physiological activity in favor of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.
2025-06-05 | GSE299102 | GEO
Project description:Dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. Yet the contribution of AMP-activated kinase (AMPK), a central energy sensor promoting catabolism, to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by a several metabolic changes, including increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity, and suggest AMPK as target to direct DC-driven tolerogenic responses in therapeutic settings.
2024-07-16 | PXD053979 | Pride
Project description:Pantothenate metabolism fuels T cell antitumor immunity
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Project description:High-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program
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Project description:Reprogramming of cancer cell metabolism toward aerobic glycolysis, i.e. the Warburg effect, is a hallmark of cancer; according to current views, the rationale for selecting such energy-inefficient metabolism is the need to increase cellular biomass to sustain production of daughter cells and proliferation. In this view, metabolic reprogramming is considered as a simple phenotypic endpoint that occurs as a consequence of signal transduction mechanisms, including oncogene-driven nutrient uptake and metabolic rewiring. A newly emerging paradigm is instead that transcriptional networks and oncogenic signaling can also be regulated downstream of metabolic pathways, that assume causative roles in controlling cancer cell behavior, above and beyond their core biochemical function. To explore possible links between glucose metabolism and nuclear gene transcription we compared immortalized mammary epithelial cells (MCF10A) and metastatic breast cancer cells (MDA-MB-231) growing in high glucose or in the presence of a widely used inhibitor of glucose uptake / glucose metabolism, 2-deoxy-glucose (2DG).
2015-03-23 | GSE59228 | GEO
Project description:Interventions: One group:5-FU
Primary outcome(s): Fasting blood-glucose
Study Design: Cohort study
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Project description:Pancreatic tumors are rewired for high-glucose metabolism and typically present with exceptionally poor prognosis. Recently, we have shown that MUC13, which is highly expressed in pancreatic tumors, promotes tumor progression via modulation of HER2 receptor tyrosine kinase activity. Herein, we investigate a novel, MUC13-mediated molecular mechanism responsible for higher glucose metabolism in pancreatic tumors. Our results demonstrate that MUC13 expression leads to the activation/nuclear translocation of NF-κB p65 and phosphorylation of IκB, which in turn upregulates the expression of important proteins (Glut-1, c-Myc, and Bcl-2) that are involved in glucose metabolism. MUC13 functionally interacts and stabilizes Glut-1 to instigate downstream events responsible for higher glucose uptake in pancreatic cancer cells. Altered MUC13 expression by overexpression and knockdown techniques effectively modulated glucose uptake, lactate secretion, and metastatic phenotypes in pancreatic cancer cells. NF-κB inhibitor, Sulfasalazine, abrogates the MUC13 and Glut-1 interaction, and attenuates events associated with MUC13-induced glucose metabolism. Pancreatic ductal adenocarcinoma (PDAC) patient tissue samples also show a positive correlation between the expression of these two proteins. These results delineate how MUC13 rewire aberrant glucose metabolism to enhance aggressiveness of pancreatic cancer and revealed a novel mechanism to develop newer therapeutic strategies for this exceptionally difficult cancer.
| S-EPMC5833644 | biostudies-literature
Project description:Alcohol metabolism directly fuels histone acetylation in the brain
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Project description:Metabolic fuels regulate insulin secretion by generating second messengers that drive insulin granule exocytosis, but the biochemical pathways involved are incompletely understood. Here we demonstrate that stimulation of rat insulinoma cells or primary rat islets with glucose or glutamine + 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (Gln + BCH) induces reductive, "counter-clockwise" tricarboxylic acid (TCA) cycle flux of glutamine to citrate. Molecular or pharmacologic suppression of isocitrate dehydrogenase-2 (IDH2), which catalyzes reductive carboxylation of 2-ketoglutarate to isocitrate, results in impairment of glucose- and Gln + BCH-stimulated reductive TCA cycle flux, lowering of NADPH levels, and inhibition of insulin secretion. Pharmacologic suppression of IDH2 also inhibits insulin secretion in living mice. Reductive TCA cycle flux has been proposed as a mechanism for generation of biomass in cancer cells. Here we demonstrate that reductive TCA cycle flux also produces stimulus-secretion coupling factors that regulate insulin secretion, including in non-dividing cells.
| S-EPMC8115731 | biostudies-literature
Project description:BackgroundTo investigate the role of DTL in the development of skin cutaneous melanoma (SKCM) and possible mechanisms.MethodsWe examined the expression of DTL in SKCM in The Cancer Genome Atlas (TCGA) and Oncomine database and analyzed the relationship between DTL expression and melanoma prognosis. Furthermore, we silenced the DTL gene by RNA interference in A375 cells and investigated the effect of DTL silencing on the biological function of melanoma cells.ResultsThe expression of DTL in SKCM was upregulated in the tumor tissues compared with the paired normal tissues. Survival analysis showed that higher DTL expression in SKCM patients was associated with poor clinical outcome compared with the lower DTL expression group. Silencing of DTL in A375 cells significantly inhibited the melanoma cell growth and proliferation ability, and also significantly decreased the total glucose consumption and lactate production. Gene set enrichment analysis (GSEA) showed that MYC targets gene set pathway was highly enriched in the DTL high expression group. The expression levels of some MYC targets-related oncogenes, including c-MYC, HK1, HK2, PGK1, ENO1, LDHA, IDH1, ACLY, and HMGCR, were reduced in the A375 cells with knockdown DTL and upregulated in SKCM tissues with high DTL expression, and there was a positive correlation between them.ConclusionsAn important role is played by DTL in promoting melanoma cell growth and glucose metabolism, possibly through activation of the MYC target pathway.
| S-EPMC8848355 | biostudies-literature