bims-mascan Biomed News
on Mass spectrometry in cancer research
Issue of 2019‒12‒15
twenty-six papers selected by
Giovanny Rodriguez Blanco
The Beatson Institute for Cancer Research


  1. Cell Metab. 2019 Dec 03. pii: S1550-4131(19)30617-5. [Epub ahead of print]
    Snaebjornsson MT, Janaki-Raman S, Schulze A.
      Altered lipid metabolism is among the most prominent metabolic alterations in cancer. Enhanced synthesis or uptake of lipids contributes to rapid cancer cell growth and tumor formation. Lipids are a highly complex group of biomolecules that not only constitute the structural basis of biological membranes but also function as signaling molecules and an energy source. Here, we summarize recent evidence implicating altered lipid metabolism in different aspects of the cancer phenotype and discuss potential strategies by which targeting lipid metabolism could provide a therapeutic window for cancer treatment.
    Keywords:  cancer; fatty acid desaturation; fatty acids; lipid metabolism; lipid remodeling; mevalonate
    DOI:  https://doi.org/10.1016/j.cmet.2019.11.010
  2. Cell Metab. 2019 Nov 28. pii: S1550-4131(19)30619-9. [Epub ahead of print]
    LeBoeuf SE, Wu WL, Karakousi TR, Karadal B, Jackson SR, Davidson SM, Wong KK, Koralov SB, Sayin VI, Papagiannakopoulos T.
      Rewiring of metabolic pathways is a hallmark of tumorigenesis as cancer cells acquire novel nutrient dependencies to support oncogenic growth. A major genetic subtype of lung adenocarcinoma with KEAP1/NRF2 mutations, which activates the endogenous oxidative stress response, undergoes significant metabolic rewiring to support enhanced antioxidant production. We demonstrate that cancers with high antioxidant capacity exhibit a general dependency on exogenous non-essential amino acids (NEAAs) that is driven by the Nrf2-dependent secretion of glutamate through system xc- (XCT), which limits intracellular glutamate pools that are required for NEAA synthesis. This dependency can be therapeutically targeted by dietary restriction or enzymatic depletion of individual NEAAs. Importantly, limiting endogenous glutamate levels by glutaminase inhibition can sensitize tumors without alterations in the Keap1/Nrf2 pathway to dietary restriction of NEAAs. Our findings identify a metabolic strategy to therapeutically target cancers with genetic or pharmacologic activation of the Nrf2 antioxidant response pathway by restricting exogenous sources of NEAAs.
    Keywords:  Keap1; NRF2; amino acid synthesis; asparaginase; glutamate; glutaminase; lung cancer; metabolism; non-essential amino acids; oxidative stress; system x(c)(−)
    DOI:  https://doi.org/10.1016/j.cmet.2019.11.012
  3. Br J Cancer. 2019 Dec 10.
    Koundouros N, Poulogiannis G.
      A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K-AKT-mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.
    DOI:  https://doi.org/10.1038/s41416-019-0650-z
  4. Cell Mol Life Sci. 2019 Dec 10.
    Hua W, Ten Dijke P, Kostidis S, Giera M, Hornsveld M.
      Metastasis is the most frequent cause of death in cancer patients. Epithelial-to-mesenchymal transition (EMT) is the process in which cells lose epithelial integrity and become motile, a critical step for cancer cell invasion, drug resistance and immune evasion. The transforming growth factor-β (TGFβ) signaling pathway is a major driver of EMT. Increasing evidence demonstrates that metabolic reprogramming is a hallmark of cancer and extensive metabolic changes are observed during EMT. The aim of this review is to summarize and interconnect recent findings that illustrate how changes in glycolysis, mitochondrial, lipid and choline metabolism coincide and functionally contribute to TGFβ-induced EMT. We describe TGFβ signaling is involved in stimulating both glycolysis and mitochondrial respiration. Interestingly, the subsequent metabolic consequences for the redox state and lipid metabolism in cancer cells are found to be in favor of EMT as well. Combined we illustrate that a better understanding of the mechanistic links between TGFβ signaling, cancer metabolism and EMT holds promising strategies for cancer therapy, some of which are already actively being explored in the clinic.
    Keywords:  Cancer; Choline metabolism; EMT; Glycolysis; Lipid metabolism; Mitochondrial metabolism; Signal transduction; TGFβ
    DOI:  https://doi.org/10.1007/s00018-019-03398-6
  5. J Proteome Res. 2019 Dec 10.
    Guan S, Jia B, Chao K, Zhu X, Tang J, Li M, Wu L, Xing L, Liu K, Zhang L, Wang X, Gao X, Huang M.
      Identification of new biomarkers may help to early diagnosis of inflammatory bowel disease (IBD). In this study, ultra-high-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UPLC - QTOF - MS) were used to analyze the untargeted lipidomics and compare plasma lipid profiles between IBD patients and control subjects. The principal component analysis and partial least-squares-discriminant analysis were carried out to distinguish IBD patients from control subjects. Using univariate and multivariate analysis, 55 significantly different metabolites from five lipid classes, fatty acyls (n=19), glycerophospholipids (n=5), prenol lipids (n=10), sphingolipids (n=2), and sterol lipids (n=19) were identified. Forty four of the 55 metabolites were analyzed by receiver operating characteristic (ROC) curve and of area under curve (AUC) > 0.80. After validation in an independent cohort, IBD patients were differentiated from the control subjects by significantly altered plasma level of Palmitic acid, 7alpha,25-dihydroxycholesterol, 20-hydroxyeicosatetraenoic (HETE) -d6, (+/-)5,6- epoxy-eicosatrienoic acid (EpETrE), docosahexaenoic acid (DHA), 9-heptadecylenic acid, Lactucaxanthin, alpha-Carotene, Traumatic acid, and Neoquassin with both sensitivity and specificity above 80%. Pathway analysis suggested that IBD dysregulation was related to the biosynthesis of primary bile acid, the metabolism of arachidonic acid, the metabolism of sphingolipid, fatty acid elongation and glycerophospholipid metabolism. Our results suggest the lipidomic profiling of patients plasma could be a potential method for IBD diagnosis.
    DOI:  https://doi.org/10.1021/acs.jproteome.9b00440
  6. Br J Cancer. 2019 Dec 10.
    Vettore L, Westbrook RL, Tennant DA.
      An abundant supply of amino acids is important for cancers to sustain their proliferative drive. Alongside their direct role as substrates for protein synthesis, they can have roles in energy generation, driving the synthesis of nucleosides and maintenance of cellular redox homoeostasis. As cancer cells exist within a complex and often nutrient-poor microenvironment, they sometimes exist as part of a metabolic community, forming relationships that can be both symbiotic and parasitic. Indeed, this is particularly evident in cancers that are auxotrophic for particular amino acids. This review discusses the stromal/cancer cell relationship, by using examples to illustrate a number of different ways in which cancer cells can rely on and contribute to their microenvironment - both as a stable network and in response to therapy. In addition, it examines situations when amino acid synthesis is driven through metabolic coupling to other reactions, and synthesis is in excess of the cancer cell's proliferative demand. Finally, it highlights the understudied area of non-proteinogenic amino acids in cancer metabolism and their potential role.
    DOI:  https://doi.org/10.1038/s41416-019-0620-5
  7. Br J Cancer. 2019 Dec 10.
    Berndt N, Egners A, Mastrobuoni G, Vvedenskaya O, Fragoulis A, Dugourd A, Bulik S, Pietzke M, Bielow C, van Gassel R, Damink SWO, Erdem M, Saez-Rodriguez J, Holzhütter HG, Kempa S, Cramer T.
      BACKGROUND: Metabolic alterations can serve as targets for diagnosis and cancer therapy. Due to the highly complex regulation of cellular metabolism, definite identification of metabolic pathway alterations remains challenging and requires sophisticated experimentation.METHODS: We applied a comprehensive kinetic model of the central carbon metabolism (CCM) to characterise metabolic reprogramming in murine liver cancer.
    RESULTS: We show that relative differences of protein abundances of metabolic enzymes obtained by mass spectrometry can be used to assess their maximal velocity values. Model simulations predicted tumour-specific alterations of various components of the CCM, a selected number of which were subsequently verified by in vitro and in vivo experiments. Furthermore, we demonstrate the ability of the kinetic model to identify metabolic pathways whose inhibition results in selective tumour cell killing.
    CONCLUSIONS: Our systems biology approach establishes that combining cellular experimentation with computer simulations of physiology-based metabolic models enables a comprehensive understanding of deregulated energetics in cancer. We propose that modelling proteomics data from human HCC with our approach will enable an individualised metabolic profiling of tumours and predictions of the efficacy of drug therapies targeting specific metabolic pathways.
    DOI:  https://doi.org/10.1038/s41416-019-0659-3
  8. Bioanalysis. 2019 Nov;11(21): 1967-1980
    Liu J, Li J, Tran C, Aluri K, Zhang X, Clausen V, Zlatev I, Guan L, Chong S, Charisse K, Wu JT, Najarian D, Xu Y.
      Aim: Advancements in RNA interference therapeutics have triggered development of improved bioanalytical methods for oligonucleotide metabolite profiling and high-throughput quantification in biological matrices. Results & methodology: HPLC coupled with high-resolution mass spectrometry (LC-HRMS) methods were developed to investigate the metabolism of a REVERSIR™ molecule in vivo. Plasma and tissue samples were extracted using solid-phase extraction followed by LC-HRMS analysis for metabolite profiling and quantification. The method was qualified from 10 to 5000 ng/ml (plasma) and 100 to 50000 ng/g (liver and kidney). In rat liver, intra and interday accuracy ranged from 80.9 to 118.5% and 88.4 to 111.9%, respectively, with acceptable precision (<20% CV). Conclusion: The LC-HRMS method can be applied for metabolite profiling and quantification of oligonucleotides in biological matrices.
    Keywords:  RNAi; mass spectrometry; metabolite profiling; oligonucleotide; pharmacokinetic; siRNA; small interfering RNA
    DOI:  https://doi.org/10.4155/bio-2019-0137
  9. Methods. 2019 Dec 06. pii: S1046-2023(19)30188-4. [Epub ahead of print]
    Thomas SP, Haws SA, Borth LE, Denu JM.
      Advances in mass spectrometry (MS) have revolutionized the ability to measure global changes in histone post-translational modifications (PTMs). The method routinely quantifies over 60 modification states in a single sample, far exceeding the capabilities of traditional western blotting. Thus, MS-based histone analysis has become an increasingly popular tool for understanding how genetics and environmental factors influence epigenetic states. However, histone proteomics experiments exhibit unique challenges, such as batch-to-batch reproducibility, accurate peak integration, and noisy data. Here, we discuss the steps of histone PTM analysis, from sample preparation and peak integration to data analysis and validation. We outline a set of best practices for ensuring data quality, accurate normalization, and robust statistics. Using these practices, we quantify histone modifications in 5 human cell lines, revealing that each cell line exhibits a unique epigenetic signature. We also provide a reproducible workflow for histone PTM analysis in the form of an R script, which is freely available at https://github.com/DenuLab/HistoneAnalysisWorkflow.
    Keywords:  Histone post-translational modification (PTM); acetylation; data analysis; data visualization; mass spectrometry; methylation
    DOI:  https://doi.org/10.1016/j.ymeth.2019.12.001
  10. J Biol Chem. 2019 Dec 09. pii: jbc.RA119.011137. [Epub ahead of print]
    Aldahl J, Mi J, Pineda A, Kim WK, Olson A, Hooker E, He Y, Yu EJ, Le V, Lee DH, Geradts J, Sun Z.
      Co-occurrence of aberrant hepatocyte growth factor (HGF)/MET proto-oncogene receptor tyrosine kinase (MET) and Wnt/β-catenin signaling pathways has been observed in advanced and metastatic prostate cancers. This co-occurrence positively correlates with prostate cancer progression and castration-resistant prostate cancer (CRPC) development. However, the biological consequences of these abnormalities in these disease processes remain largely unknown. Here, we investigated the aberrant activation of HGF/MET and Wnt/β-catenin cascades in prostate tumorigenesis by using a newly generated mouse model in which both murine Met transgene and stabilized β-catenin are conditionally co-expressed in prostatic epithelial cells. These compound mice displayed accelerated prostate tumor formation and invasion compared with their littermates that expressed only stabilized β-catenin. RNA-Seq and qRT-PCR analyses revealed increased expression of genes associated with tumor cell proliferation, progression, and metastasis. Moreover, Wnt signaling pathways were robustly enriched in prostate tumor samples from the compound mice. ChIP-qPCR experiments revealed increased β-catenin recruitment within the regulatory regions of the Myc gene in tumor cells of the compound mice. Interestingly, the occupancy of MET on the Myc promoter also appeared in the compound mouse tumor samples, implicating a novel role of MET in β-catenin-mediated transcription. Results from implanting prostate graft tissues derived from the compound mice and controls into HGF-transgenic mice further uncovered that HGF induces prostatic oncogenic transformation and cell growth. These results indicate a role of HGF/MET in β-catenin-mediated prostate cancer cell growth and progression and implicate a molecular mechanism whereby nuclear MET promotes aberrant Wnt/β-catenin signaling-mediated prostate tumorigenesis.
    Keywords:  MET proto-oncogene receptor tyrosine kinase (MET); Wnt signaling; beta-catenin (B-catenin ); cell signaling; hepatocyte growth factor/scatter factor (HGF/SF); metastasis; mouse; prostate cancer; transgenic mice; tumorigenesis
    DOI:  https://doi.org/10.1074/jbc.RA119.011137
  11. Sci Rep. 2019 Dec 12. 9(1): 18944
    Carbonetti G, Wilpshaar T, Kroonen J, Studholme K, Converso C, d'Oelsnitz S, Kaczocha M.
      Prostate cancer (PCa) is defined by dysregulated lipid signaling and is characterized by upregulation of lipid metabolism-related genes including fatty acid binding protein 5 (FABP5), fatty acid synthase (FASN), and monoacylglycerol lipase (MAGL). FASN and MAGL are enzymes that generate cellular fatty acid pools while FABP5 is an intracellular chaperone that delivers fatty acids to nuclear receptors to enhance PCa metastasis. Since FABP5, FASN, and MAGL have been independently implicated in PCa progression, we hypothesized that FABP5 represents a central mechanism linking cytosolic lipid metabolism to pro-metastatic nuclear receptor signaling. Here, we show that the abilities of FASN and MAGL to promote nuclear receptor activation and PCa metastasis are critically dependent upon co-expression of FABP5 in vitro and in vivo. Our findings position FABP5 as a key driver of lipid-mediated metastasis and suggest that disruption of lipid signaling via FABP5 inhibition may constitute a new avenue to treat metastatic PCa.
    DOI:  https://doi.org/10.1038/s41598-019-55418-x
  12. Cancers (Basel). 2019 Dec 05. pii: E1945. [Epub ahead of print]11(12):
    Muthu M, Kumar R, Syed Khaja AS, Gilthorpe JD, Persson JL, Nordström A.
      Glutamate-ammonia ligase (GLUL) is important for acid-base homeostasis, ammonia detoxification, cell signaling, and proliferation. Here, we reported that GLUL ablation conferred resistance to several anticancer drugs in specific cancer cell lines while leaving other cell lines non-resistant to the same drugs. To understand the biochemical mechanics supporting this drug resistance, we compared drug-resistant GLUL knockout (KO) A549 non-small-cell lung carcinoma (NSCLC) cells with non-resistant GLUL KO H1299 NSCLC cells and found that the resistant A549 cells, to a larger extent, depended on exogenous glucose for proliferation. As GLUL activity is linked to the tricarboxylic acid (TCA) cycle via reversed glutaminolysis, we probed carbon flux through both glycolysis and TCA pathways by means of 13C5 glutamine, 13C5 glutamate, and 13C6 glucose tracing. We observed increased labeling of malate and aspartate in A549 GLUL KO cells, whereas the non-resistant GLUL KO H1299 cells displayed decreased 13C-labeling. The malate and aspartate shuttle supported cellular NADH production and was associated with cellular metabolic fitness. Inhibition of the malate-aspartate shuttle with aminooxyacetic acid significantly impacted upon cell viability with an IC50 of 11.5 μM in resistant GLUL KO A549 cells compared to 28 μM in control A549 cells, linking resistance to the malate-aspartate shuttle. Additionally, rescuing GLUL expression in A549 KO cells increased drug sensitivity. We proposed a novel metabolic mechanism in cancer drug resistance where the increased capacity of the malate-aspartate shuttle increased metabolic fitness, thereby facilitating cancer cells to escape drug pressure.
    Keywords:  GLUL; LC-MS; NSCLC; drug resistance; glutamine; glycolysis; metabolism; metabolomics; targeted metabolomics
    DOI:  https://doi.org/10.3390/cancers11121945
  13. Br J Cancer. 2019 Dec 10.
    Frezza C.
      In the last decade, the field of cancer metabolism transformed itself from being a description of the metabolic features of cancer cells to become a key component of cellular transformation. Now, the potential role of this field in cancer biology is ready to be unravelled.
    DOI:  https://doi.org/10.1038/s41416-019-0667-3
  14. Cells. 2019 Dec 09. pii: E1601. [Epub ahead of print]8(12):
    Curtarello M, Tognon M, Venturoli C, Silic-Benussi M, Grassi A, Verza M, Minuzzo S, Pinazza M, Brillo V, Tosi G, Ferrazza R, Guella G, Iorio E, Godfroid A, Sounni NE, Amadori A, Indraccolo S.
      Anti-angiogenic therapy triggers metabolic alterations in experimental and human tumors, the best characterized being exacerbated glycolysis and lactate production. By using both Liquid Chromatography-Mass Spectrometry (LC-MS) and Nuclear Magnetic Resonance (NMR) analysis, we found that treatment of ovarian cancer xenografts with the anti-Vascular Endothelial Growth Factor (VEGF) neutralizing antibody bevacizumab caused marked alterations of the tumor lipidomic profile, including increased levels of triacylglycerols and reduced saturation of lipid chains. Moreover, transcriptome analysis uncovered up-regulation of pathways involved in lipid metabolism. These alterations were accompanied by increased accumulation of lipid droplets in tumors. This phenomenon was reproduced under hypoxic conditions in vitro, where it mainly depended from uptake of exogenous lipids and was counteracted by treatment with the Liver X Receptor (LXR)-agonist GW3965, which inhibited cancer cell viability selectively under reduced serum conditions. This multi-level analysis indicates alterations of lipid metabolism following anti-VEGF therapy in ovarian cancer xenografts and suggests that LXR-agonists might empower anti-tumor effects of bevacizumab.
    Keywords:  LXR agonist; bevacizumab; lipid droplets; metabolism; ovarian cancer
    DOI:  https://doi.org/10.3390/cells8121601
  15. Molecules. 2019 Dec 10. pii: E4524. [Epub ahead of print]24(24):
    Sun R, Huang J, Yang N, He J, Yu X, Feng S, Xie Y, Wang G, Ye H, Aa J.
      High-calorie diet, circadian rhythms and metabolic features are intimately linked. However, the mediator(s) between nutritional status, circadian rhythms and metabolism remain largely unknown. This article aims to clarify the key metabolic pathways bridging nutritional status and circadian rhythms based on a combination of metabolomics and molecular biological techniques. A mouse model of high-fat diet-induced obesity was established and serum samples were collected in obese and normal mice at different zeitgeber times. Gas chromatography/mass spectrometry, multivariate/univariate data analyses and metabolic pathway analysis were used to reveal changes in metabolism. Metabolites involved in the metabolism of purines, carbohydrates, fatty acids and amino acids were markedly perturbed in accordance with circadian related variations, among which purine catabolism showed a typical oscillation. What's more, the rhythmicity of purine catabolism dampened in the high-fat diet group. The expressions of clock genes and metabolic enzymes in the liver were measured. The mRNA expression of Xanthine oxidase (Xor) was highly correlated with the rhythmicity of Clock, Rev-erbα and Bmal1, as well as the metabolites involved in purine catabolism. These data showed that a high-fat diet altered the circadian rhythm of metabolic pathways, especially purine catabolism. It had an obvious circadian oscillation and a high-fat diet dampened its circadian rhythmicity. It was suggested that circadian rhythmicity of purine catabolism is related to circadian oscillations of expression of Xor, Uox and corresponding clock genes.
    Keywords:  GC/MS; circadian rhythms; high-fat diet; metabolomics; obesity; purine catabolism
    DOI:  https://doi.org/10.3390/molecules24244524
  16. Sci Rep. 2019 Dec 10. 9(1): 18699
    Shiratori R, Furuichi K, Yamaguchi M, Miyazaki N, Aoki H, Chibana H, Ito K, Aoki S.
      Most cancer cells rely on glycolysis to generate ATP, even when oxygen is available. However, merely inhibiting the glycolysis is insufficient for the eradication of cancer cells. One main reason for this is that cancer cells have the potential to adapt their metabolism to their environmental conditions. In this study, we investigated how cancer cells modify their intracellular metabolism when glycolysis is suppressed, using PANC-1 pancreatic cancer cells and two other solid tumor cell lines, A549 and HeLa. Our study revealed that glycolytically suppressed cells upregulated mitochondrial function and relied on oxidative phosphorylation (OXPHOS) to obtain the ATP necessary for their survival. Dynamic changes in intracellular metabolic profiles were also observed, reflected by the reduced levels of TCA cycle intermediates and elevated levels of most amino acids. Glutamine and glutamate were important for this metabolic reprogramming, as these were largely consumed by influx into the TCA cycle when the glycolytic pathway was suppressed. During the reprogramming process, activated autophagy was involved in modulating mitochondrial function. We conclude that upon glycolytic suppression in multiple types of tumor cells, intracellular energy metabolism is reprogrammed toward mitochondrial OXPHOS in an autophagy-dependent manner to ensure cellular survival.
    DOI:  https://doi.org/10.1038/s41598-019-55296-3
  17. Sci Rep. 2019 Dec 09. 9(1): 18635
    Yu-Lee LY, Lee YC, Pan J, Lin SC, Pan T, Yu G, Hawke DH, Pan BF, Lin SH.
      Disseminated tumor cells (DTCs) undergo a dormant state in the distant metastatic site(s) before becoming overt metastatic diseases. In prostate cancer (PCa), bone metastasis can occur years after prostatectomy, suggesting that bone may provide dormancy-inducing factors. To search for these factors, we prepared conditioned media (CM) from calvariae. Using live-cell imaging, we found that Calvarial-CM treatment increased cellular quiescence in C4-2B4 PCa cells. Mass spectrometry analysis of Calvarial-CM identified 132 secreted factors. Western blot and ELISA analyses confirmed the presence of several factors, including DKK3, BMP1, neogenin and vasorin in the Calvarial-CM. qRT-PCR analysis of total calvariae versus isolated osteoblasts showed that DKK3, BMP1, vasorin and neogenin are mainly expressed by osteoblasts, while MIA, LECT1, NGAL and PEDF are expressed by other calvarial cells. Recombinant human DKK3, BMP1, vasorin, neogenin, MIA and NGAL treatment increased cellular quiescence in both C4-2b and C4-2B4 PCa cells. Mechanistically, DKK3, vasorin and neogenin, but not BMP1, increased dormancy through activating the p38MAPK signaling pathway. Consistently, DKK3, vasorin and neogenin failed to induce dormancy in cells expressing dominant-negative p38αMAPK while BMP1 remained active, suggesting that BMP1 uses an alternative dormancy signaling pathway. Thus, bone secretes multiple dormancy-inducing factors that employ distinct signaling pathways to induce DTC dormancy in bone.
    DOI:  https://doi.org/10.1038/s41598-019-54566-4
  18. Inflammation. 2019 Dec 11.
    Wang S, Xiao C, Liu C, Li J, Fang F, Lu X, Zhang C, Xu F.
      Sepsis or septic shock is often accompanied by organ dysfunction, among which acute kidney injury (AKI) is the most frequent event that appears early during sepsis. To harness urinary metabolic profiling to discover potential biomarkers of septic acute kidney injury in pediatric patients at intensive care units, we collected urine samples from 27 septic children with AKI and 30 septic children without AKI. We used ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) for profiling and multiple regression analysis to explore the potential biomarkers of sepsis with AKI. We identified a clear distinction in the UPLC-QTOF/MS results for septic children with and without AKI after the development of sepsis, specifically 18 and 17 metabolites with different levels at 12 and 24 h, respectively. Metabolic pathways associated with septic AKI included lipid metabolism, particularly processes involving glycerophospholipid metabolism. L-Histidine, DL-indole-3-lactic acid, trimethylamine N-oxide, and caprylic acid were uncovered as potential biomarkers of septic AKI at 12 h, while gentisaldehyde, 3-ureidopropionate, N4-acetylcytidine, and 3-methoxy-4-hydroxyphenylglycol sulfate were identified as potential candidates at 24 h. We further found that combinations of metabolites were more effective diagnostic marker compared with individual metabolites, with an area under the receiver operating characteristics curve of 0.905 and 0.97 at 12 and 24 h, respectively. Our results indicated that metabolomic analysis could be a promising approach for identifying diagnostic biomarkers of pediatric septic AKI and helped elucidate the pathological mechanisms involved.
    Keywords:  acute kidney injury; biomarkers; metabolomics; pediatric; sepsis; urine
    DOI:  https://doi.org/10.1007/s10753-019-01144-5
  19. J Lipid Res. 2019 Dec 09. pii: jlr.RA119000311. [Epub ahead of print]
    Choucair I, Nemet I, Li L, Cole MA, Skye SM, Kirsop JD, Fischbach M, Gogonea V, Brown JM, Tang WHW, Hazen SL.
      Bile acids (BAs) serve multiple biological functions, ranging from absorption of lipids and fat-soluble vitamins, to serving as signaling molecules through the direct activation of dedicated cellular receptors. Synthesized by both host and microbial pathways, BAs are increasingly appreciated to participate in the regulation of numerous pathways relevant to metabolic diseases including lipid and glucose metabolism, energy expenditure and inflammation, pathways relevant to metabolic diseases.  Quantitative analyses of BAs in biological matrices can be problematic due to their unusual and diverse physicochemical properties, making optimization of a method that shows good accuracy, precision, efficiency of extraction, and minimized matrix effects across structurally distinct human and murine BAs challenging.  Herein we develop and clinically validate a stable isotope dilution liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for the quantitative analysis of numerous primary and secondary BAs in both human and mouse biological matrices. We also utilize this tool to investigate gut microbiota participation in generation of structurally specific BAs in both humans and mice. We examine circulating levels of specific BAs and in a clinical case-control study of age- and gender-matched type 2 diabetics (T2DM) versus non-diabetics. BAs whose circulating levels are associated with T2DM include numerous 12α-hydroxyl BAs (taurocholic acid, taurodeoxycholic acid, glycodeoxycholic acid, deoxycholic acid and 3-ketodeoxycholic acid), while taurohyodeoxycholic acid was negatively associated with diabetes. The LC/MS/MS based platform described should serve as a robust, high throughput investigative tool for studying the potential involvement of structurally specific BAs and the gut microbiome on both physiological and disease processes.
    Keywords:  Bile acids and salts; Diabetes; Mass spectrometry; Microbial metabolome; Steroid hormones
    DOI:  https://doi.org/10.1194/jlr.RA119000311
  20. Br J Cancer. 2019 Dec 10.
    Harris AL.
      Cancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.
    DOI:  https://doi.org/10.1038/s41416-019-0666-4
  21. Mol Metab. 2019 Nov 29. pii: S2212-8778(19)30949-4. [Epub ahead of print]
    Schulze A.
      
    DOI:  https://doi.org/10.1016/j.molmet.2019.11.017
  22. Cancer Cell. 2019 Dec 09. pii: S1535-6108(19)30481-7. [Epub ahead of print]36(6): 582-596
    Boison D, Yegutkin GG.
      Adenosine is a key metabolic and immune-checkpoint regulator implicated in the tumor escape from the host immune system. Major gaps in knowledge that impede the development of effective adenosine-based therapeutics include: (1) lack of consideration of redundant pathways controlling ATP and adenosine levels; (2) lack of distinction between receptor-dependent and -independent effects of adenosine, and (3) focus on extracellular adenosine without consideration of intracellular metabolism and compartmentalization. In light of current clinical trials, we provide an overview of adenosine metabolism and point out the need for a more careful evaluation of the entire purinome in emerging cancer therapies.
    Keywords:  adenosine; adenosine kinase; adenosine receptors; biochemistry; cancer; epigenetics; immune checkpoint; intracellular; metabolism; therapy
    DOI:  https://doi.org/10.1016/j.ccell.2019.10.007
  23. Nat Rev Cancer. 2019 Dec 13.
    Fane M, Weeraratna AT.
      Most cancers arise in individuals over the age of 60. As the world population is living longer and reaching older ages, cancer is becoming a substantial public health problem. It is estimated that, by 2050, more than 20% of the world's population will be over the age of 60 - the economic, healthcare and financial burdens this may place on society are far from trivial. In this Review, we address the role of the ageing microenvironment in the promotion of tumour progression. Specifically, we discuss the cellular and molecular changes in non-cancerous cells during ageing, and how these may contribute towards a tumour permissive microenvironment; these changes encompass biophysical alterations in the extracellular matrix, changes in secreted factors and changes in the immune system. We also discuss the contribution of these changes to responses to cancer therapy as ageing predicts outcomes of therapy, including survival. Yet, in preclinical studies, the contribution of the aged microenvironment to therapy response is largely ignored, with most studies designed in 8-week-old mice rather than older mice that reflect an age appropriate to the disease being modelled. This may explain, in part, the failure of many successful preclinical therapies upon their translation to the clinic. Overall, the intention of this Review is to provide an overview of the interplay that occurs between ageing cell types in the microenvironment and cancer cells and how this is likely to impact tumour metastasis and therapy response.
    DOI:  https://doi.org/10.1038/s41568-019-0222-9
  24. Anal Bioanal Chem. 2019 Dec 10.
    Züllig T, Trötzmüller M, Köfeler HC.
      Lipids are amongst the most important organic compounds in living organisms, where they serve as building blocks for cellular membranes as well as energy storage and signaling molecules. Lipidomics is the science of the large-scale determination of individual lipid species, and the underlying analytical technology that is used to identify and quantify the lipidome is generally mass spectrometry (MS). This review article provides an overview of the crucial steps in MS-based lipidomics workflows, including sample preparation, either liquid-liquid or solid-phase extraction, derivatization, chromatography, ion-mobility spectrometry, MS, and data processing by various software packages. The associated concepts are discussed from a technical perspective as well as in terms of their application. Furthermore, this article sheds light on recent advances in the technology used in this field and its current limitations. Particular emphasis is placed on data quality assurance and adequate data reporting; some of the most common pitfalls in lipidomics are discussed, along with how to circumvent them.
    Keywords:  Chromatography; LC-MS; Lipidomics; Mass spectrometry; Shotgun lipidomics
    DOI:  https://doi.org/10.1007/s00216-019-02241-y
  25. Br J Cancer. 2019 Dec 10.
    Zhang Z, Liu R, Shuai Y, Huang Y, Jin R, Wang X, Luo J.
      BACKGROUND: Glutamine is an abundant and versatile nutrient in cancer cells. Head and neck squamous cell carcinoma (HNSCC) was reported to be dependent on mainly glucose, not glutamine, for producing the energy required for survival and proliferation.METHODS: The roles of ASCT2 (SLC1A5) and associated glutamine metabolism were determined by the MTT, colony formation, glutamine uptake, intracellular glutathione, ROS detection, immunofluorescence, immunohistochemistry, and apoptosis enzyme-linked immunosorbent assays as well as animal studies.
    RESULTS: We found that glutamine is also critical for HNSCC. In this study, ASCT2, an amino acid transporter responsible for glutamine transport, in addition to LAT1 and GLS, is overexpressed in HNSCC and associated with poor survival. Using both in vivo and in vitro models, we found that knocking down ASCT2 by shRNAs or miR-137 or the combination of silencing ASCT2 and pharmacologically inhibiting SNAT2 via a small-molecule antagonist called V-9302 significantly suppressed intracellular glutamine levels and downstream glutamine metabolism, including glutathione production; these effects attenuated growth and proliferation, increased apoptosis and autophagy, and increased oxidative stress and mTORC1 pathway suppression in HNSCC. Additionally, silencing ASCT2 improved the response to cetuximab in HNSCC.
    CONCLUSIONS: In summary, ASCT2-dependent glutamine uptake and subsequent glutamine metabolism are essential for HNSCC tumorigenesis, and the combination of glutamine uptake inhibitors and cetuximab presents a promising strategy for improving the outcomes of HNSCC patients.
    DOI:  https://doi.org/10.1038/s41416-019-0637-9
  26. Biomolecules. 2019 Dec 03. pii: E822. [Epub ahead of print]9(12):
    Battista N, Bari M, Bisogno T.
      The lipid signal is becoming increasingly crowded as increasingly fatty acid amide derivatives are being identified and considered relevant therapeutic targets. The identification of N-arachidonoyl-ethanolamine as endogenous ligand of cannabinoid type-1 and type-2 receptors as well as the development of different -omics technologies have the merit to have led to the discovery of a huge number of naturally occurring N-acyl-amines. Among those mediators, N-acyl amino acids, chemically related to the endocannabinoids and belonging to the complex lipid signaling system now known as endocannabinoidome, have been rapidly growing for their therapeutic potential. Here, we review the current knowledge of the mechanisms for the biosynthesis and inactivation of the N-acyl amino acids, as well as the various molecular targets for some of the N-acyl amino acids described so far.
    Keywords:  N-acyl Glycines; N-acyl Serines; N-acyl amino acids
    DOI:  https://doi.org/10.3390/biom9120822