The metabolic reprogramming of amino acids is an important component of tumor metabolism. Branched-chain amino acids (BCAAs) perform important functions in tumor progression. They are the important amino donor and are involved in the synthesis of various non-essential amino acids, nucleotides, and polyamines to satisfy the increased demand for nitrogen sources. This review summarizes the studies related to abnormalities in BCAA metabolism during tumorigenesis and the potential therapeutic targets. The expression of BCAA transporters was significantly upregulated in tumor cells, which increases BCAA uptake. High expression of the BCAA transaminases is prevalent in various tumors, however, the dehydrogenation step of BCAA catabolism is inhibited in tumors. This review shows that BCAA metabolic reprogramming is an important tumor metabolic feature, and metabolic genes of BCAAs play a crucial role in tumor metabolism, representing a good auxiliary target for early clinical diagnosis and treatment. In addition, BCAAs are indispensable for maintaining immune system function, and dietary supplementation with BCAAs can enhance the activity of immune cells. Therefore, BCAA supplementation in tumor patients may affect the interaction between the immune system and tumors.

Tumor cells display profound changes in the metabolism of branched-chain amino acids (BCAA). However, how these changes are regulated to facilitate tumorigenesis is not yet completely understood. Here, we identified pancreatic progenitor cell differentiation and proliferation factor (PPDPF) as a BCAA-responsive protein through extensive screening using stable isotope labeling with amino acids in cell culture (SILAC). PPDPF is upregulated in cholangiocarcinoma to enhance the malignant phenotype of cholangiocarcinoma cells by activating the mTORC1 signaling pathway. Metabolic flux analysis and mechanistic studies revealed that PPDPF prevented the interaction between MCCA and MCCB, thus inhibiting leucine catabolism and activating mTORC1 signaling. Moreover, upon amino acid starvation, ariadne RBR E3 ubiquitin protein ligase 2 (ARIH2) and OTU deubiquitinase 4 (OTUD4) cooperatively regulated the stability of the PPDPF protein by modulating its ubiquitination. Additionally, monocytes/macrophage-derived IL-10 increased the BCAA content in cholangiocarcinoma cells and stabilized the PPDPF protein, even under amino acid starvation conditions. Knockout of PPDPF or restriction of leucine intake significantly inhibits the progression of cholangiocarcinoma in a mouse model. Collectively, we discovered a novel role for PPDPF in promoting the progression of cholangiocarcinoma by activating mTORC1 signaling through the inhibition of leucine catabolism. The present study suggests that targeting PPDPF or decreasing dietary leucine intake may provide a new strategy to improve the treatment efficacy of cholangiocarcinoma.

Prostate cancer (PCa) has emerged as a predominant cause of cancer-related mortality among men globally. The mechanisms of branched-chain amino acids (BCAAs) contributing to the development of PCa remain inadequately elucidated. The objective of this study was to examine the involvement of BCAAs and BCAT2 in tumorigenesis. BCAAs exhibited elevated expression levels in PCa tissues and cells. Among the critical enzymes involved in the BCAA metabolic pathway, only BCAT2 demonstrated significant expression in PCa and was closely associated with tumor progression and patient prognosis. RNA sequencing along with related functional experiments indicated that BCAT2 can inhibit autophagy, autophagy-related apoptosis, and ferroptosis in PCa. Furthermore, the results of co-immunoprecipitation, mass spectrometry, and other methodologies established that PCBP1, as a downstream protein interacting with BCAT2, co-regulates the PI3K/AKT pathway, thereby influencing progression of PCa. Moreover, BCAT2 interacted with PCBP1 at Leucine 239 to collaboratively regulate the PI3K/AKT signaling pathway, which is crucial for the initiation and progression of PCa. Targeting BCAT2 may represent a promising therapeutic strategy to prevent proliferation of PCa.

Renal cell carcinoma (RCC), a therapeutically recalcitrant genitourinary malignancy, exemplifies the profound interplay between oncogenic signaling and metabolic adaptation. Emerging evidence positions metabolic reprogramming as a central axis of RCC pathogenesis, characterized by dynamic shifts in nutrient utilization that transcend canonical Warburg physiology to encompass lipid anabolism, glutamine auxotrophy, and microenvironment-driven metabolic plasticity. This orchestrated rewiring of cellular energetics sustains tumor proliferation under hypoxia while fostering immunosuppression through metabolite-mediated T cell exhaustion and myeloid-derived suppressor cell activation. Crucially, RCC exhibits metabolic heterogeneity across histological subtypes and intratumoral regions-a feature increasingly recognized as a determinant of therapeutic resistance. Our review systematically deciphers the molecular architecture of RCC metabolism, elucidating how VHL/HIF axis mutations, mTOR pathway dysregulation, and epigenetic modifiers converge to reshape glucose flux, lipid droplet biogenesis, and amino acid catabolism. We present novel insights into spatial metabolic zonation within RCC tumors, where pseudohypoxic niches engage in lactate shuttling and cholesterol efflux to adjacent vasculature, creating pro-angiogenic and immunosuppressive microdomains. Therapeutically, we evaluate first-in-class inhibitors targeting rate-limiting enzymes in de novo lipogenesis and glutamine metabolism, while proposing biomarker-driven strategies to overcome compensatory pathway activation. We highlight the synergy between glutaminase inhibitors and PD-1 blockade in reinvigorating CD8+ T cell function, and the role of lipid-loaded cancer-associated fibroblasts in shielding tumors from ferroptosis. Finally, we outline a translational roadmap integrating multi-omics profiling, functional metabolomics, and spatial biology to match metabolic vulnerabilities with precision therapies.

Poria cocos polysaccharides (PCP), the main component of Poria cocos, possess a variety of biological activities, including antitumor, immunomodulatory, and antioxidant effects. However, whether PCP has an antiaging effect remains unclear. Here, we studied the beneficial effects and the mechanism of PCP on delaying aging using the Drosophila model. The results showed that the dietary supplementation of PCP significantly extended the lifespan, improved the climbing ability, attenuated intestinal barrier dysfunction, alleviated gastrointestinal acid-base imbalance, and prevented intestinal stem cells (ISCs) hyperproliferation. In addition, PCP notably increased the activities of SOD and CAT and reduced the content of MDA. Furthermore, RNA-Seq showed that PCP supplementation led to the differential expression of 638 genes. KEGG analysis revealed that these differentially expressed genes were strongly enriched in the signaling pathway of cofactor biosynthesis. Among these genes, the expression of the branched-chain amino acid transferase-encoding gene (bcat) was significantly downregulated. The bcat-knockdown prolonged the flies' lifespan, while bcat-overexpression reduced the lifespan. Interestingly, PCP addition can rescue the flies' lifespan in the background of bcat-overexpression. Taken together, our data indicate that PCP delays aging by enhancing the antioxidant ability and suppressing the expression of the bcat gene in Drosophila.

Metabolic reprogramming enables tumour cells to sustain their continuous proliferation and adapt to the ever-changing microenvironment. Branched-chain amino acids (BCAAs) and their metabolites are involved in intracellular protein synthesis and catabolism, signal transduction, epigenetic modifications, and the maintenance of oxidative homeostasis. Alterations in BCAA metabolism can influence the progression of various tumours. However, how BCAA metabolism is dysregulated differs among depending on tumour type; for example, it can manifest as decreased BCAA metabolism leading to BCAA accumulation, or as enhanced BCAA uptake and increased catabolism. In this review, we describe the role of BCAA metabolism in the progression of different tumours. As well as discuss how BCAA metabolic reprogramming drives tumour therapy resistance and evasion of the antitumour immune response, and how these pro-cancer effects are achieved in part by activating the mTORC signalling pathway. In-depth investigations into the potential mechanisms by which BCAA metabolic reprogramming affects tumorigenesis and tumour progression can enhance our understanding of the relationship between metabolism and cancer and provide new strategies for cancer therapy.

Glutamate and glutamine are critical metabolites in gliomas, each serving distinct roles in tumor biology. Separate quantification of these metabolites using in vivo MR spectroscopy (MRS) at clinical field strengths (≤ 3T) is hindered by their molecular similarity, resulting in overlapping, hence indistinguishable, spectral peaks.

To develop an MRS imaging (MRSI) protocol to map glutamate and glutamine separately at 3T within clinically feasible time, using J-modulation to enhance spectral differentiation, demonstrate its reliability/reproducibility, and quantify the metabolites in glioma subregions.

Prospective.

Phantoms, 5 healthy subjects, and 30 patients with suspected glioma. IDH wild-type glioblastoma cases were evaluated to establish a uniform group.

3T, Research protocol: 2D 1H sLASER MRSI (40 and 120 ms TE) with water reference, 3D T1-weighted and 2D T2-weighted. Trial-screening process: T1-weighted, T1-weighted contrast-enhanced, T2-weighted, FLAIR.

Spectral simulations and phantom measurements were performed to design and validate the protocol. Spectral quality/fitting parameters for scan-rescan measurements were obtained using LCModel. The proposed long-TE data were compared with short-TE data. BraTS Toolkit was employed for fully automated tumor segmentation.

Scan-rescan comparison was performed using Bland-Altman analysis. LCModel coefficient of modeling covariance (CMC) between glutamate and glutamine was mapped to evaluate their model interactions for each spectral fitting. Metabolite levels in tumor subregions were compared using one-way ANOVA and Kruskal-Wallis. A p value < 0.05 was considered statistically significant.

Spectral quality/fitting parameters and metabolite levels were highly consistent between scan-rescan measurements. A negative association between glutamate and glutamine models at short TE (CMC = -0.16 ± 0.06) was eliminated at long TE (0.01 ± 0.05). Low glutamate in tumor subregions (non-enhancing-tumor-core: 5.35 ± 4.45 mM, surrounding-non-enhancing-FLAIR-hyperintensity: 7.39 ± 2.62 mM, and enhancing-tumor: 7.60 ± 4.16 mM) was found compared to contralateral (10.84 ± 2.94 mM), whereas glutamine was higher in surrounding-non-enhancing-FLAIR-hyperintensity (9.17 ± 6.84 mM) and enhancing-tumor (7.20 ± 4.42 mM), but not in non-enhancing-tumor-core (4.92 ± 3.38 mM, p = 0.18) compared to contralateral (2.94 ± 1.35 mM).

The proposed MRSI protocol (~12 min) enables separate mapping of glutamate and glutamine reliably along with other MRS-detectable standard metabolites in glioma subregions at 3T.

1 TECHNICAL EFFICACY: Stage 3.

Glioma is a highly aggressive brain tumor with limited treatment success due to its resistance to conventional therapies. Sirtuin 5 (SIRT5) has emerged as a promising target for cancer therapy, though it exhibits dual roles in different cancer types. In this study, we investigate the role of SIRT5 in glioma and its corresponding mechanisms. Our findings demonstrate that SIRT5 expression is elevated in glioma cells both in vitro and in vivo. SIRT5 knockdown significantly reduced glioma cell proliferation and enhanced sensitivity to ferroptosis. Proteomic and metabolomic analyses identifies branched-chain amino acid (BCAA) metabolism as a key downstream pathway regulated by SIRT5 through branched-chain aminotransferase 1 (BCAT1). Specifically, SIRT5-mediated desuccinylation of BCAT1 at K39 inhibits its interaction with the E3 ligase CHIP, thereby preventing BCAT1 degradation via the ubiquitin-proteasome system. Moreover, BCAT1 overexpression reverses the proliferation inhibition and ferroptosis sensitivity observed in SIRT5-knockdown cells. Clinically, we reveal a positive correlation between SIRT5 and BCAT1 levels in glioma samples, with higher expression levels predicting more advanced glioma grades and poorer clinical outcomes. Collectively, this study highlights the critical role of SIRT5 in promoting glioma progression via metabolic regulation and ferroptosis insensitivity, offering a potential therapeutic target for glioma treatment.

Heterozygous mutations in IDH1 (isocitrate dehydrogenase 1) are found in most grade II and III brain tumors. A slew of mutant IDH1 inhibitors were identified soon after the discovery of IDH1 mutations in brain tumors. But recent reports show that mutant IDH1 inhibitors reverse therapeutic vulnerabilities and activate the oncogenic transcription factor STAT3 in mutant IDH1-expressing cells. Thus, inhibiting mutant IDH1 using mutant IDH1-specific inhibitors can result in drug resistance. Therefore, to block mutant IDH1, it is imperative to identify alternative modes of therapy. In these lines, recent findings show that PROteolysis TArgeting Chimera (PROTAC) molecules can be designed to degrade target proteins in cancer cells. However, it is unknown whether degrading mutant IDH1 leads to STAT3 activation. Therefore, in this study, we asked if degrading mutant IDH1 by employing a PROTAC-based approach leads to STAT3 activation. To answer the question, we adopted the dTAG system, where we fused FKBP12F36V to mutant IDH1 proteins and used the FKBP12F36V-specific PROTAC, dTAG-13, to degrade mutant IDH1-FKBP12F36V. We assessed STAT3 activation in dTAG-13-treated cells expressing mutant IDH1-FKBP12F36V. We found that fusing FKBP12F36V-HA to mutant IDH1 phenocopies mutant IDH1 with similar expression levels, enzyme activity, and cellular localization. We observed that dTAG-13 degrades mutant IDH1-FKBP12F36V-HA in a dose- and time-responsive manner. Unlike inhibiting, degrading mutant IDH1-FKBP12F36V-HA did not lead to pSTAT3-Y705 activation. We conclude that degrading mutant IDH1 by employing a PROTAC-based approach impairs STAT3 activation. Based on these observations, we suggest that mutant IDH1-specific PROTACs can be developed to degrade mutant IDH1 in gliomas.

Glioblastoma (GBM) is a prevalent and refractory type of brain tumor. Over the past two decades, there have been minimal advancements in GBM therapy. The current standard treatment involves surgical excision followed by radiation and chemotherapy. Compared to other tumors, GBM is more challenging to treat due to the presence of glioma stem-like cells (GSCs) and the blood-brain barrier, resulting in an extremely low survival rate. Mitochondria play a critical role in tumor respiration, metabolism, and multiple signaling pathways involved in tumor formation, progression, and cell apoptosis. Consequently, mitochondria represent promising targets for developing novel anticancer agents, including those targeting oxidative phosphorylation, reactive oxygen species (ROS), mitochondrial transfer, and mitophagy. This review outlines the mitochondrial-related therapeutic targets in GBM, highlighting the potential of mitochondria as a target for GBM treatment.

To analyze the expression, biological function of branched chain amino-acid transaminase 1 (BCAT1) in oral squamous cell carcinoma (OSCC).

Real-time PCR and immunohistochemistry were used to analyze the expression of BCAT1 protein in OSCC and normal oral tissues. Based on the clinicopathological information of patients, the relationship between the expression of BCAT1 protein and other clinicopathological factors was analyzed. Real-time PCR and western blot assays were used to analyze the expression of BCAT1 gene and protein in normal human oral keratinocytes (HOK) and human OSCC cells, respectively. After BCAT1 overexpression or knockdown, the proliferation, cell cycle, migration, and invasion of human OSCC cells were analyzed by CCK8, flow cytometry, wound healing, and transwell invasion assays, respectively. After adding the BCAT1 inhibitor EGR240 to OSCC cells, the changes in cell proliferation, migration, and invasion ability in OSCC cells were analyzed. Based on the TCGA database, the involved signal pathway in BCAT1-related and BCAT1-binding genes was obtained for Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, verified by western blot assays. After inhibiting PI3K, the effect of BCAT1 on the expression of the downstream phosphorylated protein of the PI3K-Akt signaling pathway was analyzed by western blot assays. The relationship between the expression of BCAT1 and EMT-related protein of OSCC cells was also analyzed.

The expression of BCAT1 gene and protein were upregulated in OSCC tissue, which positively correlated with the pathological grade of patients with OSCC. Compared with normal oral keratinocytes, BCAT1 gene and protein were upregulated in OSCC cells. BCAT1 overexpression promoted the proliferation, migration, and invasion of OSCC cells. BCAT1 knockdown or inhibition could reduce the proliferation, migration, and invasion abilities of OSCC cells. The results of bioinformatics analysis and Western bolt showed that BCAT1 could regulate the activation of PI3K-Akt signaling pathway, and promote epithelial-mesenchymal transition (EMT) of OSCC cells.

BCAT1 could promote the proliferation, migration, and invasion of OSCC cells via PI3K-Akt signaling pathway, which is a potential therapeutic target for OSCC.

Cells integrate metabolic information into core molecular processes such as transcription to adapt to environmental changes. Chromatin, the physiological template of the eukaryotic genome, has emerged as a sensor and rheostat for fluctuating intracellular metabolites. In this review, we highlight the growing list of chromatin-associated metabolites that are derived from diverse sources. We discuss recent advances in our understanding of the mechanisms by which metabolic enzyme activities shape the chromatin structure and modifications, how specificity may emerge from their seemingly broad effects, and technologies that facilitate the study of epigenome-metabolome interplay. The recognition that metabolites are immanent components of the chromatin regulatory network has significant implications for the evolution, function, and therapeutic targeting of the epigenome.

Isocitrate dehydrogenase wild-type glioblastoma (GBM) is characterised by a heterogeneous genetic landscape resulting from dynamic competition between tumour subclones to survive selective pressures. Improvements in metabolite identification and metabolome coverage have led to increased interest in clinically relevant applications of metabolomics. Here, we use liquid chromatography-mass spectrometry and gene expression microarray to profile integrated intratumour metabolic heterogeneity, as a direct functional readout of adaptive responses of subclones to the tumour microenvironment. Multi-region surgical sampling was performed on five adult GBM patients based on pre-operative brain imaging and fluorescence-guided surgery. Polar and hydrophobic metabolites extracted from tumour fragments were assessed, followed by putative assignment of metabolite identifications based on retention times and molecular mass. Class discrimination between tumour regions through showed clear separation of tumour regions based on polar metabolite profiles. Metabolic pathway assignments revealed several significantly altered metabolites between the tumour core and invasive region to be associated with purine and pyrimidine metabolism. This proof-of-principle study assesses intratumour heterogeneity through mass spectrometry-based metabolite profiling of multi-region biopsies. Bioinformatic interpretation of the GBM metabolome has highlighted the invasive region to be biologically distinct compared to tumour core and revealed putative drug-targetable metabolic pathways associated with purine and pyrimidine metabolism.

Branched-chain amino acids (BCAAs) facilitate cancer cell proliferation and survival. Stresses, including X-irradiation, increase BCAA uptake. However, the role of BCAA metabolism in cancer cell survival remains unclear. Therefore, this study aimed to elucidate the role of the BCAA catabolic pathway in cancer cell survival following X-irradiation. X-irradiation dose-dependently dephosphorylated branched-chain α-keto acid dehydrogenaseE1α (BCKDHA) suggesting the activation of the BCKDH complex, which catalyzes the rate-determining step of BCAA catabolism. We considered that activation of BCKDH promoted the BCAA catabolism, which resulted in cancer cell resistance to X-irradiation. Consistent with this notion, cells with BCKDHA knockdown exhibited increased radiosensitivity, which was associated with the increase in mitotic catastrophe and residual double-strand breaks by decreasing cellular ATP levels after X-irradiation. Our results suggest that BCKDHA dephosphorylation promotes BCAA catabolism, leading to cell survival by mitigating DNA damage after X-irradiation. Thus, BCAA catabolic pathway may be a target for radiation therapy.

We performed gene expression profiling of mRNA/cDNA isolated from N = 117 flow sorted CLL. We detected aberrant expression of the metabolic enzyme branched chain amino acid transferase (BCAT1) in CLL with del17p/TP53mut. Through extensive validation, we confirmed the highly preferential expression of BCAT1 in CLL with del17p/TP53mut (66%) or trisomy 12 (77%). BCAT1 was not expressed in B cells isolated from normal human lymph nodes. The products of the bidirectional BCAT1 reaction, including leucine, acetyl-CoA, and alpha-ketoglutarate are known activators of MTOR. We measured an ~two-fold higher MTOR activity via normalized p-S6K levels in primary CLL with BCAT1 high versus absent expression before and after sIgM crosslinking. Through steady state metabolomics and heavy isotope metabolic tracing in primary CLL cells, we demonstrate that CLL cells are avid consumers of branched chain amino acids (BCAAs) and that BCAT1 in CLL engages in bidirectional substrate reactions. Of additional interest, CLL with aberrant BCAT1 expression were less sensitive to Venetoclax-induced apoptosis. Biologically, three CLL-derived cell lines with disruption of BCAT1 had substantially reduced growth ex vivo. Clinically, the expression of any detectable BCAT1 protein in CLL independently associated with shorter median survival (125 months versus 296 months; p < 0.0001), even after exclusion of del17p/TP53mut cases.

Multiple studies suggest a plausible connection between urologic cancers and branched-chain amino acids (BCAAs) breakdown metabolic enzymes. Nevertheless, there is scarce exploration into the variations in circulating BCAAs. In our research, we utilize bidirectional, two-sample Mendelian randomization (MR) analysis to predict the link between BCAAs levels and three distinct types of urological tumors.

The study examined data from the UK Biobank, including a comprehensive genome-wide association study (GWAS) of total BCAAs, leucine, isoleucine, and valine, alongside three urological system tumors [prostate cancer (PCa), kidney cancer, and bladder cancer] sourced from the Medical Research Council Integrative Epidemiology Unit (MRC-IEU) and FinnGen Consortium databases. The primary analytical approach involved the use of the inverse variance weighted (IVW) method, complemented by MR-PRESSO global testing and MR-Egger regression to identify potential horizontal pleiotropy. Heterogeneity was evaluated using the Cochran Q test.

The levels of circulating total BCAAs [odds ratio (OR) =1.002688, 95% confidence interval (CI): 1.000, 1.005, P=0.03], leucine (OR =1.0038, 95% CI: 1.001, 1.007, P=0.008), isoleucine (OR =1.003352, 95% CI: 1.000, 1.007, P=0.04), and valine (OR =1.00279, 95% CI: 1.001, 1.005, P=0.009) showed positive associations with PCa risk. However, there was inadequate evidence to establish a link between BCAAs and bladder or kidney cancer.

In summary, an association existed between elevated levels of circulating total BCAAs, leucine, isoleucine, and valine, and an increased risk of PCa. However, no correlation was detected between BCAAs and kidney or bladder cancer.

Leucine, isoleucine, and valine are collectively known as branched chain amino acids (BCAAs) and are often discussed in the same physiological and pathological situations. The two consecutive initial reactions of BCAA catabolism are catalyzed by the common enzymes referred to as branched chain aminotransferase (BCAT) and branched chain α-keto acid dehydrogenase (BCKDH). BCAT transfers the amino group of BCAAs to 2-ketoglutarate, which results in corresponding branched chain 2-keto acids (BCKAs) and glutamate. BCKDH performs an oxidative decarboxylation of BCKAs, which produces their coenzyme A-conjugates and NADH. BCAT2 in skeletal muscle dominantly catalyzes the transamination of BCAAs. Low BCAT activity in the liver reduces the metabolization of BCAAs, but the abundant presence of BCKDH promotes the metabolism of muscle-derived BCKAs, which leads to the production of glucose and ketone bodies. While mutations in the genes responsible for BCAA catabolism are involved in rare inherited disorders, an aberrant regulation of their enzymatic activities is associated with major metabolic disorders such as diabetes, cardiovascular disease, and cancer. Therefore, an understanding of the regulatory process of metabolic enzymes, as well as the functions of the BCAAs and their metabolites, make a significant contribution to our health.

Mitochondria are semiautonomous organelles with diverse metabolic and cellular functions including anabolism and energy production through oxidative phosphorylation. Following the pioneering observations of Otto Warburg nearly a century ago, an immense body of work has examined the role of mitochondria in cancer pathogenesis and progression. Here, we summarize the current state of the field, which has coalesced around the position that functional mitochondria are required for cancer cell proliferation. In this review, we discuss how mitochondria influence tumorigenesis by impacting anabolism, intracellular signaling, and the tumor microenvironment. Consistent with their critical functions in tumor formation, mitochondria have become an attractive target for cancer therapy. We provide a comprehensive update on the numerous therapeutic modalities targeting the mitochondria of cancer cells making their way through clinical trials.

The Glioblastoma (GBM) tumor microenvironment is heterogeneous, complex, and is being increasingly understood as a significant contributor to tumor progression. In brain tumors, the extracellular matrix contains a large concentration of Hyaluronic acid (HA) that makes it important to study its role in cancer progression. In particular, abnormal accumulation of HA is observed in gliomas and is often associated with poor prognosis. In addition, HA is a polymer and its molecular weight (MW) distribution may influence tumor cell activity. Here, we evaluate the influence of the molecular weight of HA on tumor cell metabolism. We use a 2D cell culture approach to expose the U87-MG cell line to different HA MWs (10, 60, and 500 kDa) and glucose concentrations (0, 5.5, and 25 mM). Notably, we found that HA influences GBM amino acid metabolism via reduction in LAT1 transporter protein expression. We also report an influence on mitochondrial respiration levels and a difference in the accumulation of some key products of cell metabolic activity (lactic acid, glutamic acid and succinic acid). Overall, these results indicate that HA MW can influence GBM metabolic state, with implications for cell invasion and tumor progression.

Metabolism of Branched-chain amino acids (BCAAs) is essential for the nutrient necessities in mammals. Catalytic enzymes serve to direct the whole-body BCAAs oxidation which involve in the development of various metabolic disorders. The reprogrammed metabolic elements are also responsible for malignant oncogenic processes, and favor the formation of distinctive immunosuppressive microenvironment surrounding different cancers. The impotent immune surveillance related to BCAAs dysfunction is a novel topic to investigate. Here we focus on the BCAA catalysts that contribute to metabolic changes and dysregulated immune reactions in cancer progression. We summarize the current knowledge of BCAA catalyzation, highlighting the interesting roles of BCAA metabolism in the treatment of cancers.

By using hyperpolarized 13C labeling technology, the magnetic resonance signals of 13C-labeled metabolic substrates are enhanced, which enables the in vivo monitoring of their metabolic states through magnetic resonance spectroscopy. Compared with traditional non-invasive metabolic diagnostic technologies, hyperpolarized 13C technology exhibits a number of strengths, including real-time monitoring, high precision, non-invasiveness, the absence of radiation, and the ability to assess a broader range of metabolic pathways, showing great potential for application in the treatment of glioma, stroke, Alzheimer disease, and cerebral injury. Following the approval of [1-13C]-pyruvate for clinical trials by U.S. Food and Drug Administration (FDA), there has been growing academic interest in this technology. Currently, the primary challenge lies in creating more probes and promoting their clinical applications. Herein, we outlined the principles of hyperpolarized 13C labeling technology, examined its current role in neurological metabolic diagnostics, and explored the future directions, including conducting hyperpolarized 13C magnetic resonance spectroscopy (MRS) technology at higher magnetic field strengths (such as 7T), designing additional magnetic resonance sequences specific to hyperpolarized 13C MRS, and its integration with other neuro-metabolic diagnostic methods.

In 2021, the World Health Organization classified isocitrate dehydrogenase (IDH) mutant gliomas as a distinct subgroup of tumors with genetic changes sufficient to enable a complete diagnosis. Patients with an IDH mutant glioma have improved survival which has been further enhanced by the advent of targeted therapies. IDH enzymes contribute to cellular metabolism, and mutations to specific catalytic residues result in the neomorphic production of D-2-hydroxyglutarate (D-2-HG). The accumulation of D-2-HG results in epigenetic alterations, oncogenesis and impacts the tumor microenvironment via immunological modulations. Here, we summarize the molecular, cellular, and clinical implications of IDH mutations in gliomas as well as current diagnostic techniques.

Background: Previous studies have indicated that there is an association between obesity and bladder cancer (BCa). However, the relationship between fat distribution, which is more representative of the risk of obesity, and BCa remains unclear. This study aimed to investigate the causal relationship between fat distribution and BCa, and the mediating role of circulating metabolites. Methods: The necessary data were obtained from a large Genome-Wide Association Studies (GWAS) database. Two-sample and two-step Mendelian randomization (MR) analyses were performed to investigate the association between fat distribution and BCa, as well as the mediating effect of circulating metabolites. The inverse variance weighted (IVW) method was the main analysis method. Heterogeneity tests, horizontal pleiotropy analyses, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) tests, and leave-one-out analyses were performed to assess the stability of the results. Results: The IVW method indicated that abdominal subcutaneous adipose tissue adjusted for body mass index (BMI) and height (ASATadj) and abdominal subcutaneous/gluteofemoral adipose tissue (ASAT/GFAT) increased the risk of BCa. The odds ratio (OR) for ASATadj was 1.78 (95% CI=1.27-2.50, p=0.001) and that for ASAT/GFAT was 1.64 (95% CI=1.01-2.66, p=0.047). Furthermore, two-step MR analysis revealed that the effect of ASAT/GFAT on BCa was mediated by valine (proportion mediated: 7.13%, 95% CI = 3.57%-10.69%, p=0.045). Conclusions: Our research shows that, unlike most studies which focus on visceral fat, ASAT also impacts human health by increasing the risk of BCa, with the blood metabolite valine involved in this process. Monitoring and reducing ASAT accumulation can help reducce the disease burden of BCa.

Glioblastoma (GBM) is an aggressive and highly malignant primary brain tumor characterized by rapid growth and a poor prognosis for patients. Despite advancements in treatment, the median survival time for GBM patients remains low. One of the crucial challenges in understanding and treating GBMs involves its remarkable cellular heterogeneity and adaptability. Central to the survival and proliferation of GBM cells is their ability to undergo metabolic reprogramming. Metabolic reprogramming is a process that allows cancer cells to alter their metabolism to meet the increased demands of rapid growth and to survive in the often oxygen- and nutrient-deficient tumor microenvironment. These changes in metabolism include the Warburg effect, alterations in several key metabolic pathways including glutamine metabolism, fatty acid synthesis, and the tricarboxylic acid (TCA) cycle, increased uptake and utilization of glutamine, and more. Despite the complexity and adaptability of GBM metabolism, a deeper understanding of its metabolic reprogramming offers hope for developing more effective therapeutic interventions against GBMs.

Kidney renal clear cell carcinoma (KIRC) is a major subtype of renal cell carcinoma with poor prognosis due to its invasive and metastatic nature. Despite advances in understanding the molecular underpinnings of various cancers, the role of branched-chain amino acid transferase 1 (BCAT1) in KIRC remains underexplored. This study aims to fill this gap by investigating the oncogenic role of BCAT1 in KIRC using single-cell RNA-seq data and experimental validation.

Single-cell transcriptomic data GSE159115 was utilized to investigate potential biomarkers in KIRC. After screening, we used BCAT1 as a target gene and investigated its function and mechanism in KIRC through databases such as TCGA-GTEx, using genome enrichment analysis (GSEA), genome variation analysis (GSVA), gene ontology (GO) and Kyoto Encyclopedia of the Genome (KEGG). BCAT1 expression was detected in clinical tissue samples using Western Blotting (WB) and immunohistochemical (IHC) staining techniques. We established cell lines stably overexpressing and knocking down BCAT1 and performed WB, qRT-PCR, cell scratch assay and transwell assay.

BCAT1 was highly expressed in KIRC and was associated with disease prognosis and TME. Patients with mutations in the BCAT1 gene had shorter overall survival (OS) and disease-free survival (DFS). patients with high BCAT1 expression had shorter OS, progression-free interval (PFI), and disease-specific survival (DSS). GSEA showed that BCAT1 was significantly enriched in epithelial mesenchymal transition (EMT). Bioinformatics analysis and WB and IHC staining showed that BCAT1 expression was higher in KIRC than in paracancerous tissues. In vitro experiments confirmed that BCAT1 in KIRC cells may promote EMT affecting its invasion, migration. We constructed a protein interaction network (PPI) to hypothesize proteins that may interact with BCAT1. Single-sample gene set enrichment analysis (ssGSEA) revealed the immune infiltration environment of BCAT1. Furthermore, hypomethylation of the BCAT1 promoter region in KIRC may contribute to disease progression by promoting BCAT1 expression.

BCAT1 promotes KIRC invasion and metastasis through EMT and has prognostic predictive value and potential as a biomarker. It may become a novel biomarker.

Translation of mRNA to protein is tightly regulated by transfer RNAs (tRNAs), which are subject to various chemical modifications that maintain structure, stability, and function. Deficiency of tRNA N7-methylguanosine (m7G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report that the loss of m7G rewires cellular metabolism, leading to the pathogenesis of primordial dwarfism. Conditional deletion of the catalytic enzyme Mettl1 or missense mutation of the scaffold protein Wdr4 severely impaired endochondral bone formation and bone mass accrual. Mechanistically, Mettl1 knockout decreased abundance of m7G-modified tRNAs and inhibited translation of mRNAs relating to cytoskeleton and Rho GTPase signaling. Meanwhile, Mettl1 knockout enhanced cellular energy metabolism despite incompetent proliferation and osteogenic commitment. Further exploration revealed that impairment of Rho GTPase signaling upregulated the level of branched-chain amino acid transaminase 1 (BCAT1) that rewired cell metabolism and restricted intracellular α-ketoglutarate (αKG). Supplementation of αKG ameliorated the skeletal defect of Mettl1-deficient mice. In addition to the selective translation of metabolism-related mRNAs, we further revealed that Mettl1 knockout globally regulated translation via integrated stress response (ISR) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Restoring translation by targeting either ISR or mTORC1 aggravated bone defects of Mettl1-deficient mice. Overall, our study unveils a critical role of m7G tRNA modification in bone development by regulation of cellular metabolism and indicates suspension of translation initiation as a quality control mechanism in response to tRNA dysregulation.

Background: Osteosarcoma (OS) is undeniably a formidable bone malignancy characterized by a scarcity of effective treatment options. Reprogramming of amino acid (AA) metabolism has been associated with OS development. The present study was designed to identify metabolism-associated genes (MAGs) that are differentially expressed in OS and to construct a MAG-based prognostic risk signature for this disease. Methods: Expression profiles and clinicopathological data were downloaded from Gene Expression Omnibus (GEO) and UCSC Xena databases. A set of AA MAGs was obtained from the MSigDB database. Differentially expressed genes (DEGs) in GEO dataset were identified using "limma." Prognostic MAGs from UCSC Xena database were determined through univariate Cox regression and used in the prognostic signature development. This signature was validated using another dataset from GEO database. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, single sample gene set enrichment analysis, and GDSC2 analyses were performed to explore the biological functions of the MAGs. A MAG-based nomogram was established to predict 1-, 3-, and 5-year survival. Real-time quantitative polymerase chain reaction, Western blot, and immunohistochemical staining confirmed the expression of MAGs in primary OS and paired adjacent normal tissues. Results: A total of 790 DEGs and 62 prognostic MAGs were identified. A MAG-based signature was constructed based on four MAGs: PIPOX, PSMC2, SMOX, and PSAT1. The prognostic value of this signature was successfully validated, with areas under the receiver operating characteristic curves for 1-, 3-, and 5-year survival of 0.714, 0.719, and 0.715, respectively. This MAG-based signature was correlated with the infiltration of CD56dim natural killer cells and resistance to several antiangiogenic agents. The nomogram was accurate in predictions, with a C-index of 0.77. The expression of MAGs verified by experiment was consistent with the trends observed in GEO database. Conclusion: Four AA MAGs were prognostic of survival in OS patients. This MAG-based signature has the potential to offer valuable insights into the development of treatments for OS.

Branched chain α-keto acid dehydrogenase kinase (BCKDK) is a key enzyme involved in the metabolism of branched-chain amino acids (BCAAs). Its potential as a therapeutic target and prognostic factor for a variety of cancers has been widely reported. In this study, we investigated the expression of BCKDK in clinical glioma samples and found that BCKDK was significantly overexpressed in glioblastoma (GBM) and was associated with its poor prognosis. We further found that BCKDK is phosphorylated by tyrosine protein kinase Fyn at Y151, which increases its catalytic activity and stability, and demonstrate through in vivo and in vitro experiments that BCKDK phosphorylation promotes GBM cell proliferation. In addition, we found that the levels of the metabolite N-acetyl-L-alanine (NAAL) in GBM cells with high BCKDK were higher than those in the silencing group, and silencing or inhibition of BCKDK promotes the expression of ACY1, an enzyme that catalyzes the hydrolysis of NAAL into acetic acid and alanine. Exogenous addition of NAAL can activate the ERK signaling pathway and promote the proliferation of GBM cells. Taken together, we identified a novel mechanism of BCKDK activation and found NAAL is a novel oncogenic metabolite. Our study confirms the importance of the Fyn-BCKDK-ACY1-NAAL signalling axis in the development of GBM and suggests that p-BCKDK (Y151) and NAAL can serve as potential predictors of GBM progression and prognosis.

Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

Understanding the complex bidirectional interactions between neurons and glioma cells could help to identify new therapeutic targets. Herein, the techniques and application of novel neuroscience tools implemented to study the complex interactions between brain and malignant gliomas, their results, and the potential therapeutic opportunities were reviewed.

Literature search was performed on PubMed between 2001 and 2023 using the keywords "glioma", "glioblastoma", "circuit remodeling", "plasticity", "neuron networks" and "cortical networks". Studies including grade 2 to 4 gliomas, diffuse midline gliomas, and diffuse intrinsic pontine gliomas were considered.

Glioma cells are connected through tumour microtubes and form a highly connected network within which pacemaker cells drive tumorigenesis. Unconnected cells have increased invasion capabilities. Glioma cells are also synaptically integrated within neural circuitry. Neurons promote tumour growth via paracrine and direct electrochemical mechanisms, including glutamatergic AMPA-receptors. Increased glutamate release in the tumor microenvironment and loss of peritumoral GABAergic inhibitory interneurons result in network hyperexcitability and secondary epilepsy. Functional imaging, local field potentials and subcortical mapping, performed in awake patients, have defined patterns of malignant circuit remodeling. Glioma-induced remodeling is frequent in language and even motor cortical networks, depending on tumour biological parameters, and influences functional outcomes.

These data offer new insights into glioma tumorigenesis. Future work will be needed to understand how tumor intrinsic molecular drivers influence neuron-glioma interactions but also to integrate these results to design new therapeutic options for patients.

Effectively targeting transcription factors in therapeutic interventions remains challenging, especially in core-binding factor-acute myeloid leukaemia (CBF-AML) characterized by RUNX1::ETO and CBFβ::MYH11 fusions. However, recent studies have drawn attention towards aberrant amino acid metabolisms as actionable therapeutic targets. Here, by integrating the expression profile and genetic makeup in AML cohort, we found higher BCAT1 expression in CBF-AML patients compared with other subtypes. Metabolic profiling revealed that high BCAT1 expression led to reprogrammed branch amino acid metabolism in CBF-AML and was associated with sphingolipid pathway relating to the fitness of leukaemia cells, supported by transcriptomic profiling. Mechanistically, we demonstrated in cell lines and primary patient samples that BCAT1 was directly activated by RUNX1::ETO and CBFβ::MYH11 fusion proteins similarly in a RUNX1-dependent manner through rewiring chromatin conformation at the BCAT1 gene locus. Furthermore, BCAT1 inhibition resulted in blunted cell cycle, enhanced apoptosis and myeloid differentiation of CBF-AML cells in vitro, and alleviated leukaemia burden and prolonged survival in vivo. Importantly, pharmacological inhibition of BCAT1 using the specific inhibitor Gabapentin demonstrated therapeutic effects, as evidenced by delayed leukaemia progression and improved survival in vivo. In conclusion, our study uncovers BCAT1 as a genetic vulnerability and a promising targeted therapeutic opportunity for CBF-AML.

Glioma, a malignant and infiltrative neoplasm of the central nervous system, poses a significant threat due to its high mortality rates. Branched-chain amino acid transaminase 1 (BCAT1), a key enzyme in branched-chain amino acid (BCAA) catabolism, exhibits elevated expression in gliomas and correlates strongly with poor prognosis. Nonetheless, the regulatory mechanisms underlying this increased BCAT1 expression remains incompletely understood. In this study, we reveal that ubiquitination at Lys360 facilitates BCAT1 degradation, with low ubiquitination levels contributing to high BCAT1 expression in glioma cells. The Carboxyl terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, interacts with BCAT1 via its coiled-coil (CC) domain, promoting its K48-linkage ubiquitin degradation through proteasomal pathway. Moreover, CHIP-mediated BCAT1 degradation induces metabolic reprogramming, and impedes glioma cell proliferation and tumor growth both in vitro and in vivo. Furthermore, a positive correlation is observed between low CHIP expression, elevated BCAT1 levels, and unfavorable prognosis among glioma patients. Additionally, we show that the CHIP/BCAT1 axis enhances glioma sensitivity to temozolomide by reducing glutathione (GSH) synthesis and increasing oxidative stress. These findings underscore the critical role of CHIP/BCAT1 axis in glioma cell proliferation and temozolomide sensitivity, highlighting its potential as a diagnostic marker and therapeutic target in glioma treatment.

Brain tumor-related epilepsy (BTRE) is a complication that significantly impairs the quality of life and course of treatment of patients with brain tumors. Several recent studies have shed further light on the mechanisms and pathways by which genes and biological molecules in the tumor microenvironment can cause epilepsy. Moreover, epileptic seizures have been found to promote the growth of brain tumors, making the control of epilepsy a critical factor in treating brain tumors. In this study, we summarize the previous research and recent findings concerning BTRE. Expectedly, a deeper understanding of the underlying genetic and molecular mechanisms leads to safer and more effective treatments for suppressing epileptic symptoms and tumor growth.

Long non-coding RNA (lncRNA) is a group of RNA transcripts that contribute to tumor development by post-transcriptionally regulating cancer-related genes. Nasopharyngeal carcinoma (NPC) is an epithelial tumor that occurs in the nasopharynx and is common in North Africa and Southeast Asia. The study investigated the functions of lncRNA TMPO-AS1 in NPC cell proliferation and apoptosis as well as its related competing endogenous RNA (ceRNA) mechanism.

Candidate microRNA and genes that may regulated by TMPO-AS1 were predicted with the bioinformatic tool starBase. TMPO-AS1 expression in NPC tissue, cells, nuclear part, and cytoplasmic part was measured by RT-qPCR. MTT assay, EdU assay, and flow cytometry analysis were carried out to evaluate NPC cell viability, proliferation, and apoptosis, respectively. RNA immunoprecipitation assay and luciferase reporter assay were conducted to detect the binding between TMPO-AS1 and let-7c-5p or that between let-7c-5p and BCAT1.

TMPO-AS1 and BCAT1 showed high expression in NPC tissue and cells, while let-7c-5p was downregulated in NPC. The silencing of TMPO-AS1 suppressed NPC cell proliferation while promoting cell apoptosis. Moreover, TMPO-AS1 interacted with let-7c-5p and negatively regulated let-7c-5p expression. BCAT1 was a target of let-7c-5p and was inversely regulated by let-7c-5p in NPC cells. The repressive impact of TMPO-AS1 knockdown on NPC cell growth was countervailed by overexpressed BCAT1.

TMPO-AS1 accelerates NPC cell proliferation and represses cell apoptosis by interacting with let-7c-5p to regulate BCAT1 expression.

Branched-chain amino acid transferase 1 (BCAT1) is highly expressed in multiple cancers and is associated with poor prognosis, particularly in glioblastoma (GBM). However, the post-translational modification (PTM) mechanism of BCAT1 is unknown. Here, we investigated the cross-talk mechanisms between phosphorylation and ubiquitination modifications in regulating BCAT1 activity and stability. We found that BCAT1 is phosphorylated by branched chain ketoacid dehydrogenase kinase (BCKDK) at S5, S9, and T312, which increases its catalytic and antioxidant activity and stability. STUB1 (STIP1 homology U-box-containing protein 1), the first we found and reported E3 ubiquitin ligase of BCAT1, can also be phosphorylated by BCKDK at the S19 site, which disrupts the interaction with BCAT1 and inhibits its degradation. In addition, we demonstrate through in vivo and in vitro experiments that BCAT1 phosphorylation inhibiting its ubiquitination at multiple sites is associated with GBM proliferation and that inhibition of the BCKDK-BCAT1 axis enhances the sensitivity to temozolomide (TMZ). Overall, we identified novel mechanisms for the regulation of BCAT1 modification and elucidated the importance of the BCKDK-STUB1-BCAT1 axis in GBM progression.

Glioblastoma is one of the most challenging malignancies with high aggressiveness and invasiveness and its development and progression of glioblastoma highly depends on branched-chain amino acid (BCAA) metabolism. The study aimed to investigate effects of inhibition of BCAA metabolism with cytosolic branched-chain amino acid transaminase (BCATc) Inhibitor 2 on glioblastoma, elucidate its underlying mechanisms, and explore therapeutic potential of targeting BCAA metabolism. The expression of BCATc was upregulated in glioblastoma and BCATc Inhibitor 2 precipitated apoptosis both in vivo and in vitro with the activation of Bax/Bcl2/Caspase-3/Caspase-9 axis. In addition, BCATc Inhibitor 2 promoted K63-linkage ubiquitination of mitofusin 2 (Mfn2), which subsequently caused lysosomal degradation of Mfn2, and then oxidative stress, mitochondrial fission and loss of mitochondrial membrane potential. Furthermore, BCATc Inhibitor 2 treatment resulted in metabolic reprogramming, and significant inhibition of expression of ATP5A, UQCRC2, SDHB and COX II, indicative of suppressed oxidative phosphorylation. Moreover, Mfn2 overexpression or scavenging mitochondria-originated reactive oxygen species (ROS) with mito-TEMPO ameliorated BCATc Inhibitor 2-induced oxidative stress, mitochondrial membrane potential disruption and mitochondrial fission, and abrogated the inhibitory effect of BCATc Inhibitor 2 on glioblastoma cells through PI3K/AKT/mTOR signaling. All of these findings indicate suppression of BCAA metabolism promotes glioblastoma cell apoptosis via disruption of Mfn2-mediated mitochondrial dynamics and inhibition of PI3K/AKT/mTOR pathway, and suggest that BCAA metabolism can be targeted for developing therapeutic agents to treat glioblastoma.

B-lymphocytes play major adaptive immune roles, producing antibody and driving T-cell responses. However, how immunometabolism networks support B-cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B-cell transcriptional, translational and metabolomic responses to B-cell receptor (BCR), Toll-like receptor 9 (TLR9), CD40-ligand (CD40L), interleukin-4 (IL4) or combinations thereof. T-independent BCR/TLR9 co-stimulation, which drives malignant and autoimmune B-cell states, jointly induced PD-L1 plasma membrane expression, supported by NAD metabolism and oxidative phosphorylation. BCR/TLR9 also highly induced the transaminase BCAT1, which localized to lysosomal membranes to support branched chain amino acid synthesis and mTORC1 hyperactivation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL4-triggered B-cell proliferation, IL10 expression and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B-cell phenotypes including PD-L1 checkpoint signaling, and identify BCAT1 as a novel B-cell therapeutic target.

The differentiation of high-grade glioma and brain tumors of an extracranial origin is eminent for the decision on subsequent treatment regimens. While in high-grade glioma, a surgical resection of the tumor mass is a fundamental part of current standard regimens, in brain metastasis, the burden of the primary tumor must be considered. However, without a cancer history, the differentiation remains challenging in the imaging. Hence, biopsies are common that may help to identify the tumor origin. An additional tool to support the differentiation may be of great help. For this purpose, we aimed to identify a biomarker panel based on the expression analysis of a small sample of tissue to support the pathological analysis of surgery resection specimens. Given that an aberrant glutamate signaling was identified to drive glioblastoma progression, we focused on glutamate receptors and key players of glutamate homeostasis.

Based on surgically resected samples from 55 brain tumors, the expression of ionotropic and metabotropic glutamate receptors and key players of glutamate homeostasis were analyzed by RT-PCR. Subsequently, a receiver operating characteristic (ROC) analysis was performed to identify genes whose expression levels may be associated with either glioblastoma or brain metastasis.

Out of a total of 29 glutamatergic genes analyzed, nine genes presented a significantly different expression level between high-grade gliomas and brain metastases. Of those, seven were identified as potential biomarker candidates including genes encoding for AMPA receptors GRIA1, GRIA2, kainate receptors GRIK1 and GRIK4, metabotropic receptor GRM3, transaminase BCAT1 and the glutamine synthetase (encoded by GLUL). Overall, the biomarker panel achieved an accuracy of 88% (95% CI: 87.1, 90.8) in predicting the tumor entity. Gene expression data, however, could not discriminate between patients with seizures from those without.

We have identified a panel of seven genes whose expression may serve as a biomarker panel to discriminate glioblastomas and brain metastases at the molecular level. After further validation, our biomarker signatures could be of great use in the decision making on subsequent treatment regimens after diagnosis.

Glioblastoma is an aggressive type of cancer that begins in cells called astrocytes that support nerve cells that can occur in the brain or spinal cord. It can form in the brain or spinal cord. Despite the variety of modern therapies against GBM, it is still a deadly disease. Patients usually have a median survival of approximately 14 to 15 months from the diagnosis. Glioblastoma is also known as glioblastoma multiforme. The pathogenesis contributing to the proliferation and metastasis of cancer involves aberrations of multiple signalling pathways through multiple genetic mutations and altered gene expression. The coagulant factors like thrombin and tissue factor play a noteworthy role in cancer invasion. They are produced in the microenvironment of glioma through activation of protease-activated receptors (PARs) which are activated by coagulation proteases. PARs are members of family G-protein-coupled receptors (GPCRs) that are activated by coagulation proteases. These components play a key role in tumour cell angiogenesis, migration, invasion, and interactions with host vascular cells. Further, the release of neurotransmitters is also found to regulate malignancy in gliomas. Exploration of the interplay between malignant neural circuitry with the normal conditions is also decisive in finding effective therapies for these apparently invasive tumours. The present review discusses the molecular classification of gliomas, activation of PARs by coagulation protease, and its role in metastasis of gliomas. Further, the differential involvement of neurotransmitters in the pathogenesis of gliomas has also been discussed. Targeting these molecules may present a potential therapeutic approach for the treatment of gliomas.