Rewiring of cortical glucose metabolism fuels human brain cancer growth
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ABSTRACT:
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:Glucose is essential for T cell proliferation and function, yet the metabolic fates of glucose critical for T cell responses in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as an essential arm of glucose metabolism that fuels CD8+ T cell expansion and cytotoxic function in vivo. Using stable isotope tracing, we show that CD8+ effector T (Teff) cells in vivo use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a common precursor for glycogen, glycan, and GSL biosynthesis. Blocking GSL production–by targeting the enzymes UDP-Glc pyrophosphorylase 2 (UGP2) or UDP-Glc ceramide glucosyltransferase (UGCG)–blunts CD8+ T cell expansion and cytotoxic activity without impacting glucose-dependent energy production. Mechanistically, we show that glucose-dependent GSL biosynthesis (via UGCG) maintains lipid integrity at the plasma membrane and is required for lipid raft aggregation following T cell receptor (TCR) stimulation. CD8+ T cells lacking UGCG display poor cytotoxic function and reduced tumor control in vivo. Together, our data highlight GSL biosynthesis as an essential metabolic fate for glucose–independent of energy production–required to maintain membrane lipid homeostasis and CD8+ T cell cytotoxic function in vivo.
2025-08-07 | GSE295573 | GEO
Project description:Glucose is essential for T cell proliferation and function, yet the metabolic fates of glucose critical for T cell responses in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as an essential arm of glucose metabolism that fuels CD8+ T cell expansion and cytotoxic function in vivo. Using stable isotope tracing, we show that CD8+ effector T (Teff) cells in vivo use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a common precursor for glycogen, glycan, and GSL biosynthesis. Blocking GSL production–by targeting the enzymes UDP-Glc pyrophosphorylase 2 (UGP2) or UDP-Glc ceramide glucosyltransferase (UGCG)–blunts CD8+ T cell expansion and cytotoxic activity without impacting glucose-dependent energy production. Mechanistically, we show that glucose-dependent GSL biosynthesis (via UGCG) maintains lipid integrity at the plasma membrane and is required for lipid raft aggregation following T cell receptor (TCR) stimulation. CD8+ T cells lacking UGCG display poor cytotoxic function and reduced tumor control in vivo. Together, our data highlight GSL biosynthesis as an essential metabolic fate for glucose–independent of energy production–required to maintain membrane lipid homeostasis and CD8+ T cell cytotoxic function in vivo.
2025-08-08 | PXD056453 | Pride
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
| PRJNA777572 | ENA
Project description:Osteoclasts are specialized myeloid cells with crucial roles in skeletal homeostasis and disease. Differentiation of precursor cells to osteoclasts requires extensive metabolic and epigenetic rewiring, but pathways governing these processes are poorly characterized. Here, we found that transdifferentiation into osteoclasts crucially depends on the generation of one carbon units from serine catabolized by SHMT2. Serine mediatedde novopurine synthesis fuels increased mitochondrial ATP production and ultimately SAM generation necessary for epigenetic repression of macrophage lineage genes. Intriguingly, methotrexate restrains osteoclast precursors from engaging in serine mediated one carbon metabolism, unravelling a hitherto unknown therapeutic mechanism of action. Supplementation of purine precursor metabolites which restore mitochondrial ATP generation fully rescues osteoclastogenesis of SHMT2 knockout or methotrexate inhibited cells. Together, we show an essential role of serine catabolism for metabolic epigenetic coupling in osteoclast differentiation and provide a framework how methotrexate prevents osteoclast-mediated joint destruction.
2025-09-01 | GSE243008 | GEO
Project description:High-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program
| PRJNA356311 | ENA
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
| 2667978 | ecrin-mdr-crc
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