bims-mascan Biomed News
on Mass spectrometry in cancer research
Issue of 2021–05–16
twenty-one papers selected by
Giovanny Rodríguez Blanco, University of Edinburgh
  1. Principles of stable isotope research - with special reference to protein metabolism.
  2. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.
  3. Metabolic reprogramming in renal cancer: Events of a metabolic disease.
  4. Isotope tracing in adult zebrafish reveals alanine cycling between melanoma and liver.
  5. Metabolomics in cancer research and emerging applications in clinical oncology.
  6. Research progress on FASN and MGLL in the regulation of abnormal lipid metabolism and the relationship between tumor invasion and metastasis.
  7. Intra-laboratory comparison of four analytical platforms for lipidomic quantitation using hydrophilic interaction liquid chromatography or supercritical fluid chromatography coupled to quadrupole - time-of-flight mass spectrometry.
  8. Using lipid profiling to better characterize metabolic differences in apolipoprotein E (APOE) genotype among community-dwelling older Black men.
  9. Comparative Metabolomics Revealing the Metabolic Responses of Pathogenic Bacteria to Different Antibiotics.
  10. SLFN5 regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer.
  11. Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells.
  12. Juggling with lipids, a game of Russian roulette.
  13. Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis.
  14. The role of GSK3 in metabolic pathway perturbations in cancer.
  15. Hyperhomocysteinemia-related serum metabolome alterations not normalized by short-term folic acid treatment.
  16. Potential Mechanism of S. baicalensis on Lipid Metabolism Explored via Network Pharmacology and Untargeted Lipidomics.
  17. Cellular mechanisms linking cancers to obesity.
  18. Cholesterol was identified as a biomarker in human melanocytic nevi using DESI and DESI/PI mass spectrometry imaging.
  19. Mass spectrometry analysis of circulating breast cancer cells from a Xenograft mouse model.
  20. Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer.
  21. New software tools, databases, and resources in metabolomics: updates from 2020.
  1. Clin Nutr Open Sci. 2021 Apr;36 111-125
    Principles of stable isotope research - with special reference to protein metabolism.
    Daniel J Wilkinson, Matthew S Brook, Ken Smith.
      The key to understanding the mechanisms regulating disease stems from the ability to accurately quantify the dynamic nature of the metabolism underlying the physiological and pathological changes occurring as a result of the disease. Stable isotope tracer technologies have been at the forefront of this for almost 80 years now, and through a combination of both intense theoretical and technological development over these decades, it is now possible to utilise stable isotope tracers to investigate the complexities of in vivo human metabolism from a whole body perspective, down to the regulation of sub-nanometer cellular components (i.e organelles, nucleotides and individual proteins). This review therefore aims to highlight; 1) the advances made in these stable isotope tracer approaches - with special reference given to their role in understanding the nutritional regulation of protein metabolism, 2) some considerations required for the appropriate application of these stable isotope techniques to study protein metabolism, 3) and finally how new stable isotopes approaches and instrument/technical developments will help to deliver greater clinical insight in the near future.
    Keywords:  A-V, Arterial Venous; AA, Amino Acids; AP(E), Atom percent (excess); FBR, Fractional Breakdown Rate; FSR, Fractional Synthesis Rate; GC-MS, Gas Chromatography Mass Spectrometry; LC-MS, Liquid Chromatography Mass Spectrometry; MPS, Muscle Protein Synthesis; Muscle; Protein turnover; Ra, Rate of Appearance; Rd, Rate of Disappearance; Stable isotope tracers
    DOI:  https://doi.org/10.1016/j.nutos.2021.02.005
  2. Nature. 2021 May 12.
    DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.
    Chao Mao, Xiaoguang Liu, Yilei Zhang, Guang Lei, Yuelong Yan, Hyemin Lee, Pranavi Koppula, Shiqi Wu, Li Zhuang, Bingliang Fang, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan.
      Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism1-4. Glutathione peroxidase 4 (GPX4)5,6 and ferroptosis suppressor protein 1 (FSP1)7,8 constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-L-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate-the substrate and product of dihydroorotate dehydrogenase (DHODH)-attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.
    DOI:  https://doi.org/10.1038/s41586-021-03539-7
  3. Biochim Biophys Acta Rev Cancer. 2021 May 06. pii: S0304-419X(21)00056-1. [Epub ahead of print]1876(1): 188559
    Metabolic reprogramming in renal cancer: Events of a metabolic disease.
    Samik Chakraborty, Murugabaskar Balan, Akash Sabarwal, Toni K Choueiri, Soumitro Pal.
      Recent studies have established that tumors can reprogram the pathways involved in nutrient uptake and metabolism to withstand the altered biosynthetic, bioenergetics and redox requirements of cancer cells. This phenomenon is called metabolic reprogramming, which is promoted by the loss of tumor suppressor genes and activation of oncogenes. Because of alterations and perturbations in multiple metabolic pathways, renal cell carcinoma (RCC) is sometimes termed as a "metabolic disease". The majority of metabolic reprogramming in renal cancer is caused by the inactivation of von Hippel-Lindau (VHL) gene and activation of the Ras-PI3K-AKT-mTOR pathway. Hypoxia-inducible factor (HIF) and Myc are other important players in the metabolic reprogramming of RCC. All types of RCCs are associated with reprogramming of glucose and fatty acid metabolism and the tricarboxylic acid (TCA) cycle. Metabolism of glutamine, tryptophan and arginine is also reprogrammed in renal cancer to favor tumor growth and oncogenesis. Together, understanding these modifications or reprogramming of the metabolic pathways in detail offer ample opportunities for the development of new therapeutic targets and strategies, discovery of biomarkers and identification of effective tumor detection methods.
    Keywords:  Cancer; Metabolic reprogramming; Metabolism; Renal cell carcinoma
    DOI:  https://doi.org/10.1016/j.bbcan.2021.188559
  4. Cell Metab. 2021 May 11. pii: S1550-4131(21)00180-7. [Epub ahead of print]
    Isotope tracing in adult zebrafish reveals alanine cycling between melanoma and liver.
    Fuad J Naser, Madelyn M Jackstadt, Ronald Fowle-Grider, Jonathan L Spalding, Kevin Cho, Ethan Stancliffe, Steven R Doonan, Eva T Kramer, Lijun Yao, Bradley Krasnick, Li Ding, Ryan C Fields, Charles K Kaufman, Leah P Shriver, Stephen L Johnson, Gary J Patti.
      The cell-intrinsic nature of tumor metabolism has become increasingly well characterized. The impact that tumors have on systemic metabolism, however, has received less attention. Here, we used adult zebrafish harboring BRAFV600E-driven melanoma to study the effect of cancer on distant tissues. By applying metabolomics and isotope tracing, we found that melanoma consume ~15 times more glucose than other tissues measured. Despite this burden, circulating glucose levels were maintained in disease animals by a tumor-liver alanine cycle. Excretion of glucose-derived alanine from tumors provided a source of carbon for hepatic gluconeogenesis and allowed tumors to remove excess nitrogen from branched-chain amino acid catabolism, which we found to be activated in zebrafish and human melanoma. Pharmacological inhibition of the tumor-liver alanine cycle in zebrafish reduced tumor burden. Our findings underscore the significance of metabolic crosstalk between tumors and distant tissues and establish the adult zebrafish as an attractive model to study such processes.
    Keywords:  alanine cycle; cancer; cancer metabolism; isotope tracing; melanoma; metabolite exchange; metabolomics; zebrafish
    DOI:  https://doi.org/10.1016/j.cmet.2021.04.014
  5. CA Cancer J Clin. 2021 May 13.
    Metabolomics in cancer research and emerging applications in clinical oncology.
    Daniel R Schmidt, Rutulkumar Patel, David G Kirsch, Caroline A Lewis, Matthew G Vander Heiden, Jason W Locasale.
      Cancer has myriad effects on metabolism that include both rewiring of intracellular metabolism to enable cancer cells to proliferate inappropriately and adapt to the tumor microenvironment, and changes in normal tissue metabolism. With the recognition that fluorodeoxyglucose-positron emission tomography imaging is an important tool for the management of many cancers, other metabolites in biological samples have been in the spotlight for cancer diagnosis, monitoring, and therapy. Metabolomics is the global analysis of small molecule metabolites that like other -omics technologies can provide critical information about the cancer state that are otherwise not apparent. Here, the authors review how cancer and cancer therapies interact with metabolism at the cellular and systemic levels. An overview of metabolomics is provided with a focus on currently available technologies and how they have been applied in the clinical and translational research setting. The authors also discuss how metabolomics could be further leveraged in the future to improve the management of patients with cancer.
    Keywords:  cancer; intracellular; metabolism; metabolomics
    DOI:  https://doi.org/10.3322/caac.21670
  6. Front Med. 2021 May 11.
    Research progress on FASN and MGLL in the regulation of abnormal lipid metabolism and the relationship between tumor invasion and metastasis.
    Jingyue Zhang, Yawen Song, Qianqian Shi, Li Fu.
      Tumorigenesis involves metabolic reprogramming and abnormal lipid metabolism, which is manifested by increased endogenous fat mobilization, hypertriglyceridemia, and increased fatty acid synthesis. Fatty acid synthase (FASN) is a key enzyme for the de novo synthesis of fatty acids, and monoacylglycerol esterase (MGLL) is an important metabolic enzyme that converts triglycerides into free fatty acids. Both enzymes play an important role in lipid metabolism and are associated with tumor-related signaling pathways, the most common of which is the PI3K-AKT signaling pathway. They can also regulate the immune microenvironment, participate in epithelial-mesenchymal transition, and then regulate tumor invasion and metastasis. Current literature have shown that these two genes are abnormally expressed in many types of tumors and are highly correlated with tumor migration and invasion. This article introduces the structures and functions of FASN and MGLL, their relationship with abnormal lipid metabolism, and the mechanism of the regulation of tumor invasion and metastasis and reviews the research progress of the relationship of FASN and MGLL with tumor invasion and metastasis.
    Keywords:  FASN; MGLL; lipid metabolism; metastasis; tumor invasion
    DOI:  https://doi.org/10.1007/s11684-021-0830-0
  7. Talanta. 2021 Aug 15. pii: S0039-9140(21)00288-5. [Epub ahead of print]231 122367
    Intra-laboratory comparison of four analytical platforms for lipidomic quantitation using hydrophilic interaction liquid chromatography or supercritical fluid chromatography coupled to quadrupole - time-of-flight mass spectrometry.
    Michaela Chocholoušková, Denise Wolrab, Robert Jirásko, Hana Študentová, Bohuslav Melichar, Michal Holčapek.
      The lipidomic research is currently devoting considerable effort to the harmonization that should enable the generation of comparable and accurate quantitative lipidomic data across different laboratories and regardless of the mass spectrometry-based platform used. In the present study, we systematically investigate the effects of the experimental setup on quantitative lipidomics data obtained by two lipid class separation approaches, hydrophilic interaction liquid chromatography (HILIC) and ultrahigh-performance supercritical fluid chromatography (UHPSFC), coupled to two different quadrupole - time of flight (QTOF) mass spectrometers from the same vendor. This approach is applied for measurements of 268 human plasma samples of healthy volunteers and renal cell carcinoma patients resulting in four data sets. We investigate and visualize differences among these data sets by multivariate data analysis methods, such as principal component analysis (PCA), orthogonal partial least square discriminant analysis (OPLS-DA), box plots, and logarithmic correlations of molar concentrations of individual lipid species. The results indicate that even measurements in the same laboratory for the same samples using different analytical platforms may yield slight variations in the molar concentrations determined. The normalization to a reference sample with defined lipid concentrations can further diminish these small differences, resulting in highly homogenous molar concentrations of individual lipid species. This strategy indicates a potential approach towards the reporting of comparable quantitative results independent from the quantitative approach and mass spectrometer used, which is important for a wider acceptance of lipidomics data in various biomarker inter-laboratory studies and ring trials.
    Keywords:  Hydrophilic interaction liquid chromatography; Lipidomics; Mass spectrometry; Normalization; Plasma; Quantitation; Supercritical fluid chromatography
    DOI:  https://doi.org/10.1016/j.talanta.2021.122367
  8. Geroscience. 2021 May 15.
    Using lipid profiling to better characterize metabolic differences in apolipoprotein E (APOE) genotype among community-dwelling older Black men.
    Megan M Marron, Steven C Moore, Stacy G Wendell, Robert M Boudreau, Iva Miljkovic, Akira Sekikawa, Anne B Newman.
      Apolipoprotein E (APOE) allelic variation is associated with differences in overall circulating lipids and risks of major health outcomes. Lipid profiling provides the opportunity for a more detailed description of lipids that differ by APOE, to potentially inform therapeutic targets for mitigating higher morbidity and mortality associated with certain APOE genotypes. Here, we sought to identify lipids, lipid-like molecules, and important mediators of fatty acid metabolism that differ by APOE among 278 Black men ages 70-81. Using liquid chromatography-mass spectrometry methods, 222 plasma metabolites classified as lipids, lipid-like molecules, or essential in fatty acid metabolism were detected. We applied principal factor analyses to calculate a factor score for each main lipid category. APOE was categorized as ε4 carriers (n = 83; ε3ε4 or ε4ε4), ε2 carriers (n = 58; ε2ε3 or ε2ε2), or ε3 homozygotes (n = 137; ε3ε3). Using analysis of variance, the monoacylglycerol factor, cholesterol ester factor, the factor for triacylglycerols that consist mostly of polyunsaturated fatty acids, sphingosine, and free carnitine significantly differed by APOE (p < 0.05, false discovery rate < 0.30). The monoacylglycerol factor, cholesterol ester factor, and sphingosine were lower, whereas the factor for triacylglycerols that consisted mostly of polyunsaturated fatty acids was higher among ε2 carriers than remaining participants. Free carnitine was lower among ε4 carriers than ε3 homozygotes. Lower monoacylglycerols and cholesteryl esters and higher triacylglycerols that consist mostly of polyunsaturated fatty acids may be protective metabolic characteristics of APOE ε2 carriers, whereas lower carnitine may reflect altered mitochondrial functioning among ε4 carriers in this cohort of older Black men.
    Keywords:  APOE; Apolipoprotein E; Lipids; Metabolism; Metabolites
    DOI:  https://doi.org/10.1007/s11357-021-00382-6
  9. Methods Mol Biol. 2021 ;2296 367-380
    Comparative Metabolomics Revealing the Metabolic Responses of Pathogenic Bacteria to Different Antibiotics.
    Fouad Choueiry, Xiaowei Sun, Jiangjiang Zhu.
      This protocol describes the extraction and analysis of bacterial metabolites to determine the metabolic changes pertaining to their responses to different types of antibiotics. Polar metabolites are extracted using a methanol-based extraction. Sensitive, specific, and semi-quantitative metabolite analysis was performed using a high-performance liquid chromatography coupled to a high-resolution quadrupole-Orbitrap mass spectrometry. Using our example bacteria as a demonstration, 14,528 metabolic features can be detected, and 1448 metabolites were putatively identified via basic database search. Additionally, 93 metabolites can be confidently identified via high-purity standards. Statistical analysis of these metabolites can pinpoint crucial changes in metabolic states of pathogens going through antibiotic treatment, which may assist our understanding of the antibiotic mechanism of actions from a metabolic perspective.
    Keywords:  Antibiotics; Bacteria; Liquid chromatography-mass spectrometry; Metabolic perturbation; Metabolomics
    DOI:  https://doi.org/10.1007/978-1-0716-1358-0_21
  10. Cancer Res. 2021 May 13. pii: canres.3694.2020. [Epub ahead of print]
    SLFN5 regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer.
    Rafael S Martinez, Mark J Salji, Linda Rushworth, Chara Ntala, Giovanny Rodriguez Blanco, Ann Hedley, William Clark, Paul Peixoto, Eric Hervouet, Elodie Renaude, Sonia H Y Kung, Laura C A Galbraith, Colin Nixon, Sergio Lilla, Gillian M Mackay, Ladan Fazli, Luke Gaughan, David Sumpton, Martin E Gleave, Sara Zanivan, Arnaud Blomme, Hing Y Leung.
      Androgen-deprivation therapy (ADT) is the standard of care for treatment of non-resectable prostate cancer (PCa). Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we performed a comparative proteomic analysis of three in vivo, androgen receptor (AR)-responsive orthograft models of matched hormone-naive PCa and CRPC. Differential proteomic analysis revealed that distinct molecular mechanisms, including amino acid (AA) and fatty acid (FA) metabolism, are involved in the response to ADT in the different models. Despite this heterogeneity, Schlafen family member 5 (SLFN5) was identified as an AR-regulated protein in CRPC. SLFN5 expression was high in CRPC tumors and correlated with poor patient outcome. In vivo, SLFN5 depletion strongly impaired tumor growth in castrated conditions. Mechanistically, SLFN5 interacted with ATF4 and regulated the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreased intracellular levels of essential AA and impaired mTORC1 signalling in a LAT1-dependent manner. These results confirm that these orthograft models recapitulate the high degree of heterogeneity observed in CRPC patients and further highlight SLFN5 as a clinically relevant target for CRPC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3694
  11. Front Oncol. 2021 ;11 665763
    Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells.
    Jonathan Tucci, Ting Chen, Katherine Margulis, Etan Orgel, Rebecca L Paszkiewicz, Michael D Cohen, Matthew J Oberley, Rachel Wahhab, Anthony E Jones, Ajit S Divakaruni, Cheng-Chih Hsu, Sarah E Noll, Xia Sheng, Richard N Zare, Steven D Mittelman.
       Background: There is increasing evidence that adipocytes play an active role in the cancer microenvironment. We have previously reported that adipocytes interact with acute lymphoblastic leukemia (ALL) cells, contributing to chemotherapy resistance and treatment failure. In the present study, we investigated whether part of this resistance is due to adipocyte provision of lipids to ALL cells.
    Methods: We cultured 3T3-L1 adipocytes, and tested whether ALL cells or ALL-released cytokines induced FFA release. We investigated whether ALL cells took up these FFA, and using fluorescent tagged BODIPY-FFA and lipidomics, evaluated which lipid moieties were being transferred from adipocytes to ALL. We evaluated the effects of adipocyte-derived lipids on ALL cell metabolism using a Seahorse XF analyzer and expression of enzymes important for lipid metabolism, and tested whether these lipids could protect ALL cells from chemotherapy. Finally, we evaluated a panel of lipid synthesis and metabolism inhibitors to determine which were affected by the presence of adipocytes.
    Results: Adipocytes release free fatty acids (FFA) when in the presence of ALL cells. These FFA are taken up by the ALL cells and incorporated into triglycerides and phospholipids. Some of these lipids are stored in lipid droplets, which can be utilized in states of fuel deprivation. Adipocytes preferentially release monounsaturated FFA, and this can be attenuated by inhibiting the desaturating enzyme steroyl-CoA decarboxylase-1 (SCD1). Adipocyte-derived FFA can relieve ALL cell endogenous lipogenesis and reverse the cytotoxicity of pharmacological acetyl-CoA carboxylase (ACC) inhibition. Further, adipocytes alter ALL cell metabolism, shifting them from glucose to FFA oxidation. Interestingly, the unsaturated fatty acid, oleic acid, protects ALL cells from modest concentrations of chemotherapy, such as those that might be present in the ALL microenvironment. In addition, targeting lipid synthesis and metabolism can potentially reverse adipocyte protection of ALL cells.
    Conclusion: These findings uncover a previously unidentified interaction between ALL cells and adipocytes, leading to transfer of FFA for use as a metabolic fuel and macromolecule building block. This interaction may contribute to ALL resistance to chemotherapy, and could potentially be targeted to improve ALL treatment outcome.
    Keywords:  FFA; adipocytes; leukemia; lipid droplets; microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.665763
  12. Trends Endocrinol Metab. 2021 May 10. pii: S1043-2760(21)00100-4. [Epub ahead of print]
    Juggling with lipids, a game of Russian roulette.
    Maceler Aldrovandi, Maria Fedorova, Marcus Conrad.
      Lipid peroxidation (LPO) is the molecular mechanism involved in oxidative damage of cellular membranes and the hallmark of a nonapoptotic form of cell death, known as ferroptosis. This iron-dependent cell death is an emerging strategy in cancer treatment and one of the central cell death mechanisms accounting for early cell loss and organ dysfunction in both neurodegenerative disease and ischemia-reperfusion injury. Although the biological roles of LPO products have attracted considerable attention, not only for their pathological mechanisms but also for their potential clinical application as biomarkers, the existence of a common lethal lipid death signal generated during ferroptosis remains poorly explored. A better understanding of the LPO process, however, may unleash unprecedented opportunities for therapeutic intervention of as-yet incurable diseases.
    Keywords:  ferroptosis; lipid metabolism; lipid peroxidation; polyunsaturated fatty acids; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.tem.2021.04.012
  13. Science. 2021 May 14. 372(6543): 716-721
    Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis.
    Marlies P Rossmann, Karen Hoi, Victoria Chan, Brian J Abraham, Song Yang, James Mullahoo, Malvina Papanastasiou, Ying Wang, Ilaria Elia, Julie R Perlin, Elliott J Hagedorn, Sara Hetzel, Raha Weigert, Sejal Vyas, Partha P Nag, Lucas B Sullivan, Curtis R Warren, Bilguujin Dorjsuren, Eugenia Custo Greig, Isaac Adatto, Chad A Cowan, Stuart L Schreiber, Richard A Young, Alexander Meissner, Marcia C Haigis, Siegfried Hekimi, Steven A Carr, Leonard I Zon.
      Transcription and metabolism both influence cell function, but dedicated transcriptional control of metabolic pathways that regulate cell fate has rarely been defined. We discovered, using a chemical suppressor screen, that inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) rescues erythroid differentiation in bloodless zebrafish moonshine (mon) mutant embryos defective for transcriptional intermediary factor 1 gamma (tif1γ). This rescue depends on the functional link of DHODH to mitochondrial respiration. The transcription elongation factor TIF1γ directly controls coenzyme Q (CoQ) synthesis gene expression. Upon tif1γ loss, CoQ levels are reduced, and a high succinate/α-ketoglutarate ratio leads to increased histone methylation. A CoQ analog rescues mon's bloodless phenotype. These results demonstrate that mitochondrial metabolism is a key output of a lineage transcription factor that drives cell fate decisions in the early blood lineage.
    DOI:  https://doi.org/10.1126/science.aaz2740
  14. Biochim Biophys Acta Mol Cell Res. 2021 May 11. pii: S0167-4889(21)00113-0. [Epub ahead of print] 119059
    The role of GSK3 in metabolic pathway perturbations in cancer.
    David Papadopoli, Michael Pollak, Ivan Topisirovic.
      Malignant transformation and tumor progression are accompanied by significant perturbations in metabolic programs. As such, cancer cells support high ATP turnover to construct the building blocks needed to fuel neoplastic growth. The coordination of metabolic networks in malignant cells is dependent on the collaboration with cellular signaling pathways. Glycogen synthase kinase 3 (GSK3) lies at the convergence of several signaling axes, including the PI3K/AKT/mTOR, AMPK, and Wnt pathways, which influence cancer initiation, progression and therapeutic responses. Accordingly, GSK3 modulates metabolic processes, including protein and lipid synthesis, glucose, and mitochondrial metabolism, as well as autophagy. In this review, we highlight current knowledge of the role of GSK3 in metabolic perturbations in cancer.
    Keywords:  AMPK; Cancer; GSK3; Metabolism; mTOR
    DOI:  https://doi.org/10.1016/j.bbamcr.2021.119059
  15. Metabolomics. 2021 May 09. 17(5): 47
    Hyperhomocysteinemia-related serum metabolome alterations not normalized by short-term folic acid treatment.
    A Aneesh Kumar, Vanaja R Anusree, Gopika Satheesh, Gadadharan Vijayakumar, Mahesh Chandran, Leena Simon, Subhadra Lakshmi, Madhavan R Pillai, Abdul Jaleel.
       INTRODUCTION: Hyperhomocysteinemia (HHCys) is an independent risk factor for various diseases such as cardiovascular diseases, Alzheimer's, and cancers. Folate deficiency is one of the significant reasons for HHCys. However, it is not known whether folate deficiency with HHCys is associated with any serum metabolites.
    OBJECTIVES: Our objective was to identify the metabolic alterations in people having folate deficiency with HHCys and check whether a short-term folic acid therapy could reverse those metabolic changes.
    METHODS: The study enrolled 34 participants aged between 18 and 40 years having folate deficiency (< 4.6 ng/mL) with HHCys (> 15 μmol/L) and 21 normal healthy individuals. A short-term intervention of oral folic acid (5 mg/day) was done in the HHCys group for 30 days. Untargeted metabolomics analysis of serum was performed in all study subjects before and after the folic acid treatment. Different univariate methods and the multivariable-adjusted linear regression models were employed to determine an association between homocysteine level and metabolite profile.
    RESULTS: Metabolomics analysis data showed that many metabolites involved in the biochemical pathways of lipid metabolisms such as polyunsaturated fatty acids, glycerolipids, and phospholipids were downregulated in the HHCys group. Short-term oral folic acid therapy significantly reduced their serum homocysteine level. However, the metabolic pathway alterations observed in folate-deficient HHCys-condition were unaltered even after the folic acid treatment.
    CONCLUSIONS: Our study revealed that people who have a folic acid deficiency with HHCys have an altered metabolite profile related to lipid metabolism, which cannot be reversed by short-term folic acid therapy.
    Keywords:  Folic acid; Hyperhomocysteinemia; Lipid metabolism; Untargeted metabolomics
    DOI:  https://doi.org/10.1007/s11306-021-01798-z
  16. Drug Des Devel Ther. 2021 ;15 1915-1930
    Potential Mechanism of S. baicalensis on Lipid Metabolism Explored via Network Pharmacology and Untargeted Lipidomics.
    Ping-Yuan Ge, Yi-Yu Qi, Shu-Yue Qu, Xin Zhao, Sai-Jia Ni, Zeng-Ying Yao, Rui Guo, Nian-Yun Yang, Qi-Chun Zhang, Hua-Xu Zhu.
       Background: S. baicalensis, a traditional herb, has great potential in treating diseases associated with aberrant lipid metabolism, such as inflammation, hyperlipidemia, atherosclerosis and Alzheimer's disease.
    Aim of the Study: To elucidate the mechanism by which S. baicalensis modulates lipid metabolism and explore the medicinal effects of S. baicalensis at a holistic level.
    Materials and Methods: The potential active ingredients of S. baicalensis and targets involved in regulating lipid metabolism were identified using a network pharmacology approach. Metabolomics was utilized to compare lipids that were altered after S. baicalensis treatment in order to identify significantly altered metabolites, and crucial targets and compounds were validated by molecular docking.
    Results: Steroid biosynthesis, sphingolipid metabolism, the PPAR signaling pathway and glycerolipid metabolism were enriched and predicted to be potential pathways upon which S. baicalensis acts. Further metabolomics assays revealed 14 significantly different metabolites were identified as lipid metabolism-associated elements. After the pathway enrichment analysis of the metabolites, cholesterol metabolism and sphingolipid metabolism were identified as the most relevant pathways. Based on the results of the pathway analysis, sphingolipid and cholesterol biosynthesis and glycerophospholipid metabolism were regarded as key pathways in which S. baicalensis is involved to regulate lipid metabolism.
    Conclusion: According to our metabolomics results, S. baicalensis may exert its therapeutic effects by regulating the cholesterol biosynthesis and sphingolipid metabolism pathways. Upon further analysis of the altered metabolites in certain pathways, agents downstream of squalene were significantly upregulated; however, the substrate of SQLE was surprisingly increased. By combining evidence from molecular docking, we speculated that baicalin, a major ingredient of S. baicalensis, may suppress cholesterol biosynthesis by inhibiting SQLE and LSS, which are important enzymes in the cholesterol biosynthesis pathway. In summary, this study provides new insights into the therapeutic effects of S. baicalensis on lipid metabolism using network pharmacology and lipidomics.
    Keywords:  S. baicalensis; cortex metabolomics; lipid metabolism; molecular docking; network pharmacology
    DOI:  https://doi.org/10.2147/DDDT.S301679
  17. Cell Stress. 2021 Apr 12. 5(5): 55-72
    Cellular mechanisms linking cancers to obesity.
    Xiao-Zheng Liu, Line Pedersen, Nils Halberg.
      Obesity is epidemiologically linked to 13 forms of cancer. The local and systemic obese environment is complex and likely affect tumors through multiple avenues. This includes modulation of cancer cell phenotypes and the composition of the tumor microenvironment. A molecular understanding of how obesity links to cancer holds promise for identifying candidate genes for targeted therapy for obese cancer patient. Herein, we review both the cell-autonomous and non-cell-autonomous mechanisms linking obesity and cancer as well as provide an overview of the mouse model systems applied to study this.
    Keywords:  adipokines; cancer; extracellular Matrix remodeling; inflammation; metabolism; mouse models; obesity
    DOI:  https://doi.org/10.15698/cst2021.05.248
  18. Talanta. 2021 Aug 15. pii: S0039-9140(21)00301-5. [Epub ahead of print]231 122380
    Cholesterol was identified as a biomarker in human melanocytic nevi using DESI and DESI/PI mass spectrometry imaging.
    Keke Qi, Yongmei Lv, Yun Ren, Xian Wang, Liutian Wu, Jingwen Wang, Xuan Zhang, Yifu He, Chenchen Zhang, Chengyuan Liu, Yang Pan.
      The rapid differentiation between diseased tissue and healthy normal tissue is of great importance for the intraoperative diagnosis. Herein, desorption electrospray ionization (DESI) and DESI/post-photoionization (DESI/PI) mass spectrometry imaging were combined to in situ visualize the distribution of biochemicals within the tissue regions of human melanocytic nevi under the ambient condition with a spatial resolution of around 200 μm. Plenty of polar and nonpolar lipids were found to be specifically distributed in melanocytic nevi with statistical significance and could be used to differentiate the healthy normal tissue and melanocytic nevi. Cholesterol was further confirmed to be a potential biomarker for melanocytic nevi diagnosis by multivariate statistical analysis and immunohistochemistry of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and translocator protein (TSPO) enzymes. This work provides a visual way for the diagnosis of human melanocytic nevi by lipid profiling, which benefits the understanding of the pathological mechanism of melanocytic nevi and provides a new insight to control melanin growth from the synthesis, transport, and metabolism of cholesterol.
    Keywords:  Cholesterol; DESI and DESI/PI MSI; Immunohistochemistry; Intraoperative diagnosis; Melanocytic nevi; Multivariate statistical analysis
    DOI:  https://doi.org/10.1016/j.talanta.2021.122380
  19. STAR Protoc. 2021 Jun 18. 2(2): 100480
    Mass spectrometry analysis of circulating breast cancer cells from a Xenograft mouse model.
    Cinzia Donato, Katarzyna Buczak, Alexander Schmidt, Nicola Aceto.
      Circulating tumor cells (CTCs) are precursors of metastasis in various cancer types. Many aspects regarding CTC biology remain poorly understood. Here, we describe mass spectrometric analysis of CTCs from a breast cancer xenograft mouse model, including procedures comprising CTC enrichment, separation of different CTC subpopulations, and their quantitative proteomic assessment. This protocol aims to facilitate the identification of protein content dynamics in human CTCs that are physiologically shed from tumor-bearing xenografts, providing a framework for investigating metastasis biology. For complete details on the use and execution of this protocol, please refer to Donato et al. (2020).
    Keywords:  Cancer; Cell Biology; Cell isolation; Flow Cytometry/Mass Cytometry; Mass Spectrometry; Model Organisms; Proteomics
    DOI:  https://doi.org/10.1016/j.xpro.2021.100480
  20. Front Cell Dev Biol. 2021 ;9 654337
    Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer.
    Rui Ma, Yinsheng Wu, Shanshan Li, Xilan Yu.
      Cancer cells reprogram glucose metabolism to meet their malignant proliferation needs and survival under a variety of stress conditions. The prominent metabolic reprogram is aerobic glycolysis, which can help cells accumulate precursors for biosynthesis of macromolecules. In addition to glycolysis, recent studies show that gluconeogenesis and TCA cycle play important roles in tumorigenesis. Here, we provide a comprehensive review about the role of glycolysis, gluconeogenesis, and TCA cycle in tumorigenesis with an emphasis on revealing the novel functions of the relevant enzymes and metabolites. These functions include regulation of cell metabolism, gene expression, cell apoptosis and autophagy. We also summarize the effect of glucose metabolism on chromatin modifications and how this relationship leads to cancer development. Understanding the link between cancer cell metabolism and chromatin modifications will help develop more effective cancer treatments.
    Keywords:  epigenetic modifications; gene transcription; histone modifications; metabolism; tumorigenesis
    DOI:  https://doi.org/10.3389/fcell.2021.654337
  21. Metabolomics. 2021 May 11. 17(5): 49
    New software tools, databases, and resources in metabolomics: updates from 2020.
    Biswapriya B Misra.
       BACKGROUND: Precision medicine, space exploration, drug discovery to characterization of dark chemical space of habitats and organisms, metabolomics takes a centre stage in providing answers to diverse biological, biomedical, and environmental questions. With technological advances in mass-spectrometry and spectroscopy platforms that aid in generation of information rich datasets that are complex big-data, data analytics tend to co-evolve to match the pace of analytical instrumentation. Software tools, resources, databases, and solutions help in harnessing the concealed information in the generated data for eventual translational success.
    AIM OF THE REVIEW: In this review, ~ 85 metabolomics software resources, packages, tools, databases, and other utilities that appeared in 2020 are introduced to the research community.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: In Table 1 the computational dependencies and downloadable links of the tools are provided, and the resources are categorized based on their utility. The review aims to keep the community of metabolomics researchers updated with all the resources developed in 2020 at a collated avenue, in line with efforts form 2015 onwards to help them find these at one place for further referencing and use.
    Keywords:  Annotation; Database; In silico; Metabolite; Metabolomics; Program; Recourse; Software; Tool
    DOI:  https://doi.org/10.1007/s11306-021-01796-1
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