Glucose-derived Carbon Research Articles

TMET-19. REWIRING OF CORTICAL GLUCOSE METABOLISM FUELS HUMAN BRAIN CANCER GROWTH

Abstract The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. In particular, we find that cortical tissue produces its own glucose-derived serine, whereas gliomas predominantly consume serine from the environment. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth. Combining dietary serine restriction with chemoradiation reduces brain tumor growth in mice, suggesting that such a dietary intervention could improve outcomes for patients with high grade glioma.

P300/CBP KATs Are Critical for Maturation and Differentiation of Adult Neural Progenitors.

Epigenetic modifications play a pivotal role in the process of neurogenesis. Among these modifications, reversible acetylation fine-tunes gene expression for both embryonic and adult neurogenesis. The CBP/KAT3A and its paralogue p300/KAT3B are well-known lysine acetyltransferases with transcriptional coactivation ability that engage in neural plasticity and memory. The exclusive role of their KAT activity in neurogenesis and memory could not be addressed due to the absence of a p300/CBP modulator, which can cross the blood-brain barrier. Previous work from our laboratory has shown that a small molecule activator, TTK21, specific to CBP/p300, when conjugated to glucose-derived carbon nanospheres (CSP), is efficiently delivered to the mouse brain and could induce dendritic branching and extend long-term memory. However, the molecular mechanisms of p300 acetyltransferase activity-dependent enhanced dendritogenesis are yet to be understood. Here, we report that CSP-TTK21 treatment to primary neuronal culture derived from mouse embryo enhances the expression of five critical genes: Neurod1 (central nervous system development), Tubb3 (immature neural marker), Camk2a (synaptic plasticity and LTP), Snap25 (spine morphogenesis plasticity), and Scn2a (propagation of the action potential). Activation of these genes by inducing the p300/CBP KAT activity presumably promotes the maturation and differentiation of adult neuronal progenitors and thereby the formation of long and highly branched doublecortin-positive functional neurons in the subgranular zone of the dentate gyrus.

Metal-Catalyzed Carbon Foams Synthesized from Glucose as Highly Efficient Electromagnetic Absorbers.

This paper introduces a novel method for preparing high-performance, metal-containing carbon foam wave-absorbing materials. The process involves foaming glucose through catalysis by transition metals followed by high-temperature pyrolysis. The resulting carbon foam materials exhibit a highly porous structure, which is essential for their wave-absorption properties. Notably, at a thickness of 2.0 mm, the glucose-derived carbon foam composite catalyzed by Fe and Co (GCF-CoFe) achieved a minimum reflection loss (RLmin) of -51.4 dB at 15.11 GHz, along with an effective absorption bandwidth (EAB) of 5.20 GHz, spanning from 12.80 GHz to 18.00 GHz. These impressive performance metrics indicate that this approach offers a promising pathway for developing low-density, efficient carbon foam materials for wave-absorption applications. This advancement has significant implications for fields requiring effective electromagnetic interference (EMI) shielding, stealth technology, and other related applications, potentially leading to more efficient and lightweight solutions.

Design of the Particle Size and Morphology of Hard Carbon Anode Materials for Sodium-Ion Batteries Through Hydrothermal Carbonization

With sodium-ion batteries (SIBs) finding widespread application, the demand grows for hard carbon, the most popular anode material for SIBs. Hydrothermal carbonization facilitates the production of hard carbon with desired characteristics from various sources. Despite the considerable volume of literature addressing this subject, there is a notable absence of investigations elucidating the relationship between synthesis conditions and the electrochemical characteristics of the product. Here we study systematically the influence of hydrothermal carbonization parameters on hard carbon characteristics and emphasize the potential of hard carbon as an anode material for SIBs. The initial Coulombic efficiency (ICE) is significantly affected by the particle size of the glucose-derived hard carbon, which, in turn, depends on glucose concentration in the initial solution, pH, and stirring regime. By optimizing the hydrothermal carbonization parameters, the ICE up to 91% and a good reversible capacity of ∼300 mAh g−1 in a half cell are achieved. Full cells with Na3(VO)2(PO4)2F cathode material demonstrate ICE of about 80% and reversible capacity of up to 100 mAh g−1 cath. Considering the effective performance of pouch-cell SIB prototypes based on Na3(VO)2(PO4)2F and hard carbon, hydrothermal carbonization of glucose yields hard carbon with the necessary characteristics required for its successful application in SIBs.

Coupling geometric and electronic engineering over RuNi ultrafine alloys for fast boosting hydrolytic dehydrogenation of NH3BH3

Developing a suitable catalyst for ammonia borane (AB, NH3BH3) hydrolysis and clarifying the catalytic mechanism are essential and challenging at present. In this work, RuNi nanoalloys are supported on an N/O co-coped glucose-derived carbon (g-C) with the adsorption-NaBH4 reduction method. Attributed to the particular geometric and anchoring effects, as well as the improved hydrophilicity of the multi-level porous support, the RuNi alloys are highly and firmly confined in the framework of g-C. Specifically, the optimal Ru0.25Ni0.75@g-C with an average alloy particle size of 1.4 nm exhibits pleasurable specific hydrogen evolution rate (437,990 mL min−1 gRu−1) and turnover frequency (1612.37 min−1) in NaOH aqueous solution (1.5 M) at 303 K, superior to the corresponding monometallic counterparts (i.e., Ni@g-C and Ru@g-C) and many previous results. In addition, apart from satisfactory durability, the optimal alloy catalyst delivers an encouraging apparent activation energy (28.1 kJ mol−1). Our work not only explains the geometric and electronic effects on the catalytic performance but also offers a promising catalyst for hydrogen release from liquid-phase AB.

Oral Administration of a Specific p300/CBP Lysine Acetyltransferase Activator Induces Synaptic Plasticity and Repairs Spinal Cord Injury.

TTK21 is a small-molecule activator of p300/creb binding protein (CBP) acetyltransferase activity, which, upon conjugation with a glucose-derived carbon nanosphere (CSP), can efficiently cross the blood-brain barrier and activate histone acetylation in the brain. Its role in adult neurogenesis and retention of long-term spatial memory following intraperitoneal (IP) administration is well established. In this study, we successfully demonstrate that CSP-TTK21 can be effectively administered via oral gavage. Using a combination of molecular biology, microscopy, and electrophysiological techniques, we systematically investigate the comparative efficacy of oral administration of CSP and CSP-TTK21 in wild-type mice and evaluate their functional effects in comparison to intraperitoneal (IP) administration. Our findings indicate that CSP-TTK21, when administered orally, induces long-term potentiation in the hippocampus without significantly altering basal synaptic transmission, a response comparable to that achieved through IP injection. Remarkably, in a spinal cord injury model, oral administration of CSP-TTK21 exhibits efficacy equivalent to that of IP administration. Furthermore, our research demonstrates that oral delivery of CSP-TTK21 leads to improvements in motor function, histone acetylation dynamics, and increased expression of regeneration-associated genes (RAGs) in a spinal injury rat model, mirroring the effectiveness of IP administration. Importantly, no toxic and mutagenic effects of CSP-TTK21 are observed at a maximum tolerated dose of 1 g/kg in Sprague-Dawley (SD) rats via the oral route. Collectively, these results underscore the potential utility of CSP as an oral drug delivery system, particularly for targeting the neural system.

Ultrasound-Triggered Piezoelectric Catalysis of Zinc Oxide@Glucose Derived Carbon Spheres for the Treatment of MRSA Infected Osteomyelitis.

Currently, methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis is a clinically life-threatening disease, however, long-term antibiotic treatment can lead to bacterial resistance, posing a huge challenge to treatment and public health. In this study, glucose-derived carbon spheres loaded with zinc oxide (ZnO@HTCS) are successfully constructed. This composite demonstrates the robust ability to generate reactive oxygen species (ROS) under ultrasound (US) irradiation, eradicating 99.788% ± 0.087% of MRSA within 15min and effectively treating MRSA-induced osteomyelitis infection. Piezoelectric force microscopy tests and finite element method simulations reveal that the ZnO@HTCS composite exhibits superior piezoelectric catalytic performance compared to pure ZnO, making it a unique piezoelectric sonosensitizer. Density functional theory calculations reveal that the formation of a Mott-Schottky heterojunction and an internal piezoelectric field within the interface accelerates the electron transfer and the separation of electron-hole pairs. Concurrently, surface vacancies of the composite enable the adsorption of a greater amount of oxygen, enhancing the piezoelectric catalytic effect and generating a substantial quantity of ROS. This work not only presents a promising approach for augmenting piezoelectric catalysis through construction of a Schottky heterojunction interface but also provides a novel, efficient therapeutic strategy for treating osteomyelitis.

Insights into the Electrocatalytic Activity of Fe,N-Glucose/Carbon Nanotube Hybrids for the Oxygen Reduction Reaction

Glucose-derived carbon hybrids were synthesized by hydrothermal treatment in the presence of oxidized carbon nanotubes. Additionally, iron and nitrogen functionalities were incorporated into the carbon structure using different methodologies. The introduction of iron and nitrogen in a single step under a H2 atmosphere favored the formation of quaternary nitrogen and oxidized nitrogen, whereas the incorporation of nitrogen under an N2 atmosphere after doping the hybrids with iron mainly produced pyridinic nitrogen. The samples were characterized by scanning electron microscopy, X-ray spectroscopy, adsorption isotherms, inductively coupled plasma optical emission spectrometry, and Raman spectroscopy. The presence of iron and nitrogen in the carbons increases the onset potential toward oxygen reduction in KOH 0.1 mol L−1 by 130 mV (0.83 V), in comparison to carbonized glucose, whereas the reaction mechanism shifts closer to a direct pathway and the formation of HO2− decreases to 25% (3.5 electrons). The reaction rate also increased in comparison to the carbonized glucose, as observed by the decrease in the Tafel slope value from 117 to 61 mV dec−1. Furthermore, the incorporation of iron and nitrogen in a single step enhanced the short-term performance of the prepared electrocatalysts, which may also be due to the higher relative amount of quaternary nitrogen.

Abstract 1801: Rewiring of cortical glucose metabolism fuels human brain cancer growth

Abstract The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth. Citation Format: Andrew J. Scott, Anjali Mittal, Baharan Meghdadi, Sravya Palavalasa, Abhinav Achreja, Alexandra O'Brien, Ayesha Kothari, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Donna M. Edwards, Vijay Tarnal, Nathan Qi, Theodore S. Lawrence, Sriram Venneti, Nathalie Y. Agar, Costas A. Lyssiotis, Wajd N. Al-Holou, Deepak Nagrath, Daniel R. Wahl. Rewiring of cortical glucose metabolism fuels human brain cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1801.

Abstract 4424: Differential metabolic response of triple-negative and estrogen receptor-positive breast cancer cells to abemaciclib, a CDK4/6 inhibitor

Abstract Background: Inhibition of the cell cycle kinases CDK4/6 is the standard-of-care for advanced hormone receptor-positive breast cancer. The clinical efficacy of CDK4/6 inhibitors in triple-negative breast cancer remains uncertain. Mechanisms of sensitivity and resistance are not fully understood. This study comprehensively investigated the metabolic response of triple-negative and estrogen receptor-positive breast cancer cells to abemaciclib (Abe), with the aim of providing metabolic insights for resistance mechanisms. Methods: MCF-7 (MCF) and MDA-MB-231 (MDA) cells were treated with Abe (0, 100, and 500 nM) for 1, 2, or 7 days. Cell cycle and cell senescence analyses were performed to assess drug effects. Cellular metabolism was investigated using the Seahorse assay, LC-MS/MS based targeted metabolomics, and stable isotope-assisted metabolic flux analyses with [U-13C]glutamine, [1,2-13C]glucose, and [U-13C]glucose as the tracers. Results: Abe induced cell cycle arrest at G0/G1 in both cell lines, more pronounced in MCF. Dose- and time-dependent cell senescence occurred in both treated cell lines, more pronounced in MDA. The Seahorse assay indicated that energy metabolism (assessed by oxygen consumption rate and extracellular acidification rate) was reduced in both treated cell lines. Targeted metabolomics revealed that post Abe treatment, intracellular lactate significantly decreased in both cell lines; intracellular TCA intermediates significantly decreased in MCF while being unchanged in MDA; intracellular deoxynucleotides decreased in both cell lines, to a lesser extent in MDA; cellular energy levels (assessed as the ratios of ATP/AMP, ATP/ADP, CTP/CMP, CTP/CDP) were significantly lower in MCF while remaining unchanged or increased in MDA; intracellular levels of many amino acids significantly increased in MDA while decreasing in MCF. [U-13C]glutamine flux revealed a significant decrease of intracellular glutamine-derived TCA intermediates in both treated cell lines. [1,2-13C]glucose flux indicated an enhanced oxidate pentose phosphate pathway (PPP) activity and increased de novo syntheses of purine nucleotides (ATP and GTP) in treated MDA (but not MCF). [U-13C]glucose flux suggested that while both cell lines responded to Abe with decreased anaerobic glycolysis (pyruvate converting to lactate), MDA (but not MCF) showed an enhanced capability of utilizing glucose-derived carbon to replenish TCA intermediates and increased amino acid synthesis. Conclusion: Adaptive cellular metabolism, characterized by enhanced utilization of glucose-derived carbon to replenish TCA intermediates and increased PPP activity, thus promoting biosynthesis of amino acids and purine nucleotides to maintain cellular energy and redox balance, may contribute to the intrinsic resistance of triple-negative breast cancer to CDK4/6 inhibitors. Citation Format: Jun Jiang, Xun Bao, Yuanyuan Jiang, Yang Yue, Maik Huettemann, Jing Li. Differential metabolic response of triple-negative and estrogen receptor-positive breast cancer cells to abemaciclib, a CDK4/6 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4424.

Abstract B050: Metabolic rewiring in human brain cancer

Abstract Metabolic adaptation can promote oncogenic phenotypes in glioblastoma (GBM), but the metabolic pathways utilized by GBM and how they differ from the pathways utilized in normal cortex are poorly understood. Here, we utilize in vivo stable isotope tracing in mice and patients with glioblastoma to define carbon fate and metabolic rewiring in cancer. We infused uniformly labeled 13C glucose into mice bearing orthotopic GBM patient-derived xenografts or into patients undergoing surgical resection for likely GBM. Tumor and cortex were physically separated in mice by fluorescence-guided microdissection. In humans, samples of enhancing tumor, non-enhancing tumor and normal cortex were separated intraoperatively using MRI guidance. Samples were subsequently analyzed by liquid chromatography mass spectrometry and MALDI imaging mass spectrometry to determine the downstream metabolic fates of infused 13C glucose. Of eight patients infused with 13C6-glucose, six were confirmed to have GBM while the others had non-GBM high grade gliomas. In mice and in patients, glucose-derived carbon effectively entered glycolysis and labeled glycolytic intermediates equivalently in tumor and cortex. Compared to GBM tissue, cortical tissue preferentially oxidized glucose-derived carbon in the TCA cycle and used glucose-derived carbon to synthesize the neurotransmitter GABA. Cortical tissue utilized glucose-derived carbon to synthesize the amino acid and neurotransmitter precursor serine, while GBM tissue preferentially derived serine from extracellular sources. By contrast, GBM preferentially utilized glucose-derived carbon for the synthesis of metabolites required for growth: purines, pyrimidines and NAD+/NADH. These studies are the first measurements of numerous metabolic pathways in human brain cancer and cortex and suggest that GBMs suppress the physiologic utilization of glucose carbons for ATP and neurotransmitter generation and instead use these carbons to synthesize the biomolecules they need to proliferate. Consistent with this hypothesis, eliminating dietary serine in mice slowed GBM PDX growth and forced tumors to synthesize serine from glucose, which in turn lowered tumor nucleotide and NAD+/NADH levels. Dietary serine depletion had minimal effects on cortical metabolism, consistent with glucose being the primary serine source in the normal brain. These direct measurements of metabolic pathway activity in human and mouse brain cancer reveal adaptive metabolic rewiring and new therapeutic targets. Citation Format: Andrew Scott, Anjali Mittal, Sravya Palavalasa, Baharan Meghdadi, Nathan Qi, Alexandra O'Brien, Ayesha Kothari, Nathalie Agar, Ethan Yang, Joshua Fischer, Vijay Tarnal, Wajd Al-Holou, Costas Lyssiotis, Deepak Nagrath, Daniel Wahl. Metabolic rewiring in human brain cancer [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B050.

Hole transfer layer of glucose-derived carbon enabled rapid charge transfer and hole storage for efficient water splitting

Charge recombination at the interface of oxygen evolution catalyst (OEC) and BiVO4-based photoanode is one of the great challenges to achieve efficient photoelectrochemical (PEC) water splitting due to the poor charge transfer and separation efficiency of BiVO4. Herein, a composite photoanode (NiFe/C-Mo:BiVO4) consisting of a molybdenum doped BiVO4 photoanode, an OEC interfacial layer of NiFeOOH and a tailorable hole transfer layer (HTL) made of glucose-derived carbon in between, was designed and fabricated for highly efficient PEC water splitting. The composite NiFe/C-Mo:BiVO4 photoanode exhibited the photocurrent density of 5.62 mA cm−2 at 1.23 VRHE and an outstanding photo-stability. Characterization and photoelectrochemical analyses revealed that the inserted carbon HTL, though not active for surface water oxidation kinetics, greatly suppressed the unwanted recombination of electron-hole pairs and drastically improved the transfer and storage of charge carriers at the OEC/BiVO4 interface. A surface charge separation efficiency of 89 % at 1.23 VRHE and remarkable hole storage properties were obtained. This work afforded a novel approach to the design of low-cost and sustainable HTL integrated photoanodes for efficient PEC water oxidation.

A hybrid photocatalytic system enables direct glucose utilization for methanogenesis

Integration of methanogenic archaea with photocatalysts presents a sustainable solution for solar-driven methanogenesis. However, maximizing CH4 conversion efficiency remains challenging due to the intrinsic energy conservation and strictly restricted substrates of methanogenic archaea. Here, we report a solar-driven biotic-abiotic hybrid (biohybrid) system by incorporating cadmium sulfide (CdS) nanoparticles with a rationally designed methanogenic archaeon Methanosarcina acetivorans C2A, in which the glucose synergist protein and glucose kinase, an energy-efficient route for glucose transport and phosphorylation from Zymomonas mobilis, were implemented to facilitate nonnative substrate glucose for methanogenesis. We demonstrate that the photo-excited electrons facilitate membrane-bound electron transport chain, thereby augmenting the Na+ and H+ ion gradients across membrane to enhance adenosine triphosphate (ATP) synthesis. Additionally, this biohybrid system promotes the metabolism of pyruvate to acetyl coenzyme A (AcCoA) and inhibits the flow of AcCoA to the tricarboxylic acid (TCA) cycle, resulting in a 1.26-fold augmentation in CH4 production from glucose-derived carbon. Our results provide a unique strategy for enhancing methanogenesis through rational biohybrid design and reprogramming, which gives a promising avenue for sustainably manufacturing value-added chemicals.

Unlocking the value of food waste: sustainable production of ethylene glycol over low-cost Ni–W catalysts supported on glucose-derived carbons

Low-cost Ni–W catalysts supported on glucose-based carbons were efficient for the sustainable ethylene glycol production directly from cellulose and wastes.

Facile synthesis of double yolk-shelled MnO/C microspheres as superior anode materials for lithium-ion batteries

Tenable structure design is vital in the pursuit of advanced anode materials for enhanced lithium storage, but construction of the desired architectures often faces challenges. Herein, we demonstrate the facile fabrication of double yolk-shelled MnO/C microspheres by annealing the solvothermally synthesized Mn-gluconate microspheres under Ar atmosphere, and the double or single yolk-shell structure can be easily regulated by changing the glucose amount. Benefits brought by the unique structure include enlarged surface area, hierarchical pores, abundant reaction sites and increased ion diffusion rate. Besides, combination of MnO with glucose-derived carbon could not only restrict the volume variation of MnO but also increase the electrical conductivity, bringing improved rate capability and enhanced cycling stability. Thus, a high-rate and stable capacity of 611 mAh g−1 after 500 cycles at 1 A g−1 is observed in the lithium-ion batteries adopting the presented double yolk-shelled MnO/C microspheres as the anode materials, thanks to the synergistic structure and composition advantages. Importantly, this study provides a controllable method to construct delicate multi-shelled structures with simultaneous carbon hybridization, which could be promising in fabrication of advanced electrodes for energy-related applications.

Serine synthesis pathway enzyme PHGDH is critical for muscle cell biomass, anabolic metabolism, and mTORC1 signaling.

Cells use glycolytic intermediates for anabolism, e.g., via the serine synthesis and pentose phosphate pathways. However, we still understand poorly how these metabolic pathways contribute to skeletal muscle cell biomass generation. The first aim of this study was therefore to identify enzymes that limit protein synthesis, myotube size, and proliferation in skeletal muscle cells. We inhibited key enzymes of glycolysis, the pentose phosphate pathway, and the serine synthesis pathway to evaluate their importance in C2C12 myotube protein synthesis. Based on the results of this first screen, we then focused on the serine synthesis pathway enzyme phosphoglycerate dehydrogenase (PHGDH). We used two different PHGDH inhibitors and mouse C2C12 and human primary muscle cells to study the importance and function of PHGDH. Both myoblasts and myotubes incorporated glucose-derived carbon into proteins, RNA, and lipids, and we showed that PHGDH is essential in these processes. PHGDH inhibition decreased protein synthesis, myotube size, and myoblast proliferation without cytotoxic effects. The decreased protein synthesis in response to PHGDH inhibition appears to occur mainly mechanistic target of rapamycin complex 1 (mTORC1)-dependently, as was evident from experiments with insulin-like growth factor 1 and rapamycin. Further metabolomics analyses revealed that PHGDH inhibition accelerated glycolysis and altered amino acid, nucleotide, and lipid metabolism. Finally, we found that supplementing an antioxidant and redox modulator, N-acetylcysteine, partially rescued the decreased protein synthesis and mTORC1 signaling during PHGDH inhibition. The data suggest that PHGDH activity is critical for skeletal muscle cell biomass generation from glucose and that it regulates protein synthesis and mTORC1 signaling.NEW & NOTEWORTHY The use of glycolytic intermediates for anabolism was demonstrated in both myoblasts and myotubes, which incorporate glucose-derived carbon into proteins, RNA, and lipids. We identify phosphoglycerate dehydrogenase (PHGDH) as a critical enzyme in those processes and also for muscle cell hypertrophy, proliferation, protein synthesis, and mTORC1 signaling. Our results thus suggest that PHGDH in skeletal muscle is more than just a serine-synthesizing enzyme.

TMET-03. REPROGRAMMING OF GLIOBLASTOMA GLUCOSE METABOLISM FUELS TUMOR GROWTH

Abstract Metabolic adaptation can promote oncogenic phenotypes in glioblastoma (GBM), but the metabolic pathways utilized by GBM and how they differ from the pathways utilized in normal cortex are poorly understood. Here, we utilize in vivo stable isotope tracing in mice and patients with GBM to define carbon fate and metabolic rewiring in cancer. We infused uniformly-labeled 13C glucose into mice bearing orthotopic GBM patient-derived xenografts or into patients undergoing surgical resection for likely GBM. Tumor and cortex were physically separated in mice by fluorescence-guided microdissection. In humans, samples of enhancing tumor, non-enhancing tumor and normal cortex were separated intraoperatively using MRI guidance. Samples were subsequently analyzed by liquid chromatography mass spectrometry to determine the downstream metabolic fates of infused 13C glucose. Of eight patients infused with 13C6-glucose, six were confirmed to have GBM while the others had non-GBM high grade gliomas. In mice and in patients, glucose-derived carbon effectively entered glycolysis and labeled glycolytic intermediates equivalently in tumor and cortex. Compared to GBM tissue, cortical tissue preferentially oxidized glucose-derived carbon in the TCA cycle and used glucose-derived carbon to synthesize neurotransmitters. Cortical tissue utilized glucose-derived carbon to synthesize the amino acid and neurotransmitter precursor serine, while GBM tissue derived serine from extracellular sources. By contrast, GBM tissue preferentially utilized glucose-derived carbon for the synthesis of purines, pyrimidines and NAD+/NADH. Using time-course isotope tracing studies in mice with GBM and a novel metabolic flux analysis framework, we quantified absolute metabolic fluxes in vivo and confirmed elevated nucleotide synthesis and serine salvage in GBM. Consistent with these results, eliminating dietary serine in mice slowed GBM PDX growth. These studies are the first measurements of numerous metabolic pathways in humans and indicate that GBMs suppress the physiologic utilization of glucose carbons to fuel biosynthesis, which represents a targetable metabolic liability.

N-doped 3D reduced graphene oxide supported C-encapsulated Co9S8/Co4S3 composites as anode for improved lithium storage

Carbon-coating nitrogen all-doped Co9S8/Co4S3 nanoparticles attached to reduced graphene oxide sheets (N-CS@C/G) was developed by an eco-friendly in situ methodology in this study. Glucose-derived carbon nano-wrapped layers and supported reduced graphene oxide were employed to develop a highly conductive network, whereas N dopants, Co9S8 and Co4S3 supplied additional electrochemical active sites for lithium-ion energy storage. The well-designed hetero-structured N-CS@C/G electrode with a specific surface area of 101.29 m2g−1 can contribute to notably improving the volume variation and raising electrical conductivity. Under the N-CS@C/G composites with the improved synergistic effect that served as anode, the cell exhibited progressive cycle stability of 662 mA h g−1 at 2 A g−1 when 600 cycles were completed, the high specific capacity of 1039.7 mA h g−1 at 0.05 A g−1, as well as prominent rate capability, outperforming the parallel comparison materials without the addition of glucose (N-CS) or reduced graphene oxide (N-CS@C). This study is likely to develop a distinctive avenue to produce quick and high-capacity metal sulfide anodes and boot high-performance lithium-ion batteries.

Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.

In the tumor microenvironment, adipocytes function as an alternate fuel source for cancer cells. However, whether adipocytes influence macromolecular biosynthesis in cancer cells is unknown. Here we systematically characterized the bidirectional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, isotope tracing and gene expression analysis. We report that, in OvCa cells co-cultured with adipocytes and in metastatic tumors, a part of the glucose from glycolysis is utilized for the biosynthesis of glycerol-3-phosphate (G3P). Normoxic HIF1α protein regulates the altered flow of glucose-derived carbons in cancer cells, resulting in increased glycerophospholipids and triacylglycerol synthesis. The knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of glycerophospholipid synthesis) reduced metastasis in xenograft models of OvCa. In summary, we show that, in an adipose-rich tumor microenvironment, cancer cells generate G3P as a precursor for critical membrane and signaling components, thereby promoting metastasis. Targeting biosynthetic processes specific to adipose-rich tumor microenvironments might be an effective strategy against metastasis.

Glucose-derived carbon dots as nanofillers for improved ionic conductivity in polyvinyl alcohol–based solid polymer electrolyte membranes

Glucose-derived carbon dots as nanofillers for improved ionic conductivity in polyvinyl alcohol–based solid polymer electrolyte membranes