bims-mascan Biomed News
on Mass spectrometry in cancer research
Issue of 2020–02–16
fourteen papers selected by
Giovanny Rodríguez Blanco, The Beatson Institute for Cancer Research
  1. Cell cycle regulators in cancer cell metabolism.
  2. Dynamic 13C Flux Analysis Captures the Reorganization of Adipocyte Glucose Metabolism in Response to Insulin.
  3. Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer.
  4. Lipid metabolism of leukocytes in the unstimulated and activated states.
  5. Mass Spectrometry for Biomarkers Discovery in Esophageal Squamous Cell Carcinoma.
  6. Integrated metabolomics and lipidomics profiling of hippocampus reveal metabolite biomarkers in a rat model of chronic unpredictable mild stress-induced depression.
  7. Automated untargeted stable isotope assisted lipidomics of liver cells on high glucose shows alteration of sphingolipid kinetics.
  8. Kinobead/LC-MS Phosphokinome Profiling Enables Rapid Analyses of Kinase-Dependent Cell Signaling Networks.
  9. Oncogenic Kras driven metabolic reprogramming in pancreas cancer cells utilizes cytokines from the tumor microenvironment.
  10. Control of tumor angiogenesis and metastasis through modulation of cell redox state.
  11. Role of lipids in pathophysiology, diagnosis and therapy of hepatocellular carcinoma.
  12. mTOR Regulation of Metabolism in Hematologic Malignancies.
  13. Secreted Pyruvate Kinase M2 Promotes Lung Cancer Metastasis through Activating the Integrin Beta1/FAK Signaling Pathway.
  14. Energy Stress Inhibits Ferroptotic Cell Death via AMPK Activation.
  1. Biochim Biophys Acta Mol Basis Dis. 2020 Feb 05. pii: S0925-4439(20)30060-0. [Epub ahead of print] 165715
    Cell cycle regulators in cancer cell metabolism.
    Lucia C Leal-Esteban, Lluis Fajas.
      Cancer proliferation and progression involves altered metabolic pathways as a result of continuous demand for energy and nutrients. In the last years, cell cycle regulators have been involved in the control of metabolic processes, such as glucose and insulin pathways and lipid synthesis, in addition to their canonical function controlling cell cycle progression. Here we describe recent data demonstrating the role of cell cycle regulators in the metabolic control especially in studies performed in cancer models. Moreover, we discuss the importance of these findings in the context of current cancer therapies to provide an overview of the relevance of targeting metabolism using inhibitors of the cell cycle regulation.
    Keywords:  Cancer; Cell cycle; Cyclin-dependent kinases; Cyclins; Metabolic adaptation; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1016/j.bbadis.2020.165715
  2. iScience. 2020 Jan 21. pii: S2589-0042(20)30038-9. [Epub ahead of print]23(2): 100855
    Dynamic 13C Flux Analysis Captures the Reorganization of Adipocyte Glucose Metabolism in Response to Insulin.
    Lake-Ee Quek, James R Krycer, Satoshi Ohno, Katsuyuki Yugi, Daniel J Fazakerley, Richard Scalzo, Sarah D Elkington, Ziwei Dai, Akiyoshi Hirayama, Satsuki Ikeda, Futaba Shoji, Kumi Suzuki, Jason W Locasale, Tomoyoshi Soga, David E James, Shinya Kuroda.
      Cellular metabolism is dynamic, but quantifying non-steady metabolic fluxes by stable isotope tracers presents unique computational challenges. Here, we developed an efficient 13C-tracer dynamic metabolic flux analysis (13C-DMFA) framework for modeling central carbon fluxes that vary over time. We used B-splines to generalize the flux parameterization system and to improve the stability of the optimization algorithm. As proof of concept, we investigated how 3T3-L1 cultured adipocytes acutely metabolize glucose in response to insulin. Insulin rapidly stimulates glucose uptake, but intracellular pathways responded with differing speeds and magnitudes. Fluxes in lower glycolysis increased faster than those in upper glycolysis. Glycolysis fluxes rose disproportionally larger and faster than the tricarboxylic acid cycle, with lactate a primary glucose end product. The uncovered array of flux dynamics suggests that glucose catabolism is additionally regulated beyond uptake to help shunt glucose into appropriate pathways. This work demonstrates the value of using dynamic intracellular fluxes to understand metabolic function and pathway regulation.
    Keywords:  Biological Sciences; Flux Data; Metabolic Flux Analysis; Metabolomics
    DOI:  https://doi.org/10.1016/j.isci.2020.100855
  3. Cancer Cell. 2020 Feb 10. pii: S1535-6108(19)30581-1. [Epub ahead of print]37(2): 147-156
    Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer.
    Sharanya Sivanand, Matthew G Vander Heiden.
      Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers, with changes in branched-chain amino acid metabolism specifically affecting cancer cell state as well as systemic metabolism in individuals with malignancy. This review highlights key concepts surrounding the current understanding of branched-chain amino acid metabolism and its role in cancer.
    Keywords:  branched-chain amino acids; cancer metabolism; epigenetics; metabolism
    DOI:  https://doi.org/10.1016/j.ccell.2019.12.011
  4. Anal Bioanal Chem. 2020 Feb 14.
    Lipid metabolism of leukocytes in the unstimulated and activated states.
    Juan Carlos Alarcon-Barrera, Johannes H von Hegedus, Hilde Brouwers, Evelyne Steenvoorden, Andreea Ioan-Facsinay, Oleg A Mayboroda, Alejandro Ondo-Mendez, Martin Giera.
      Lipidomics has emerged as a powerful technique to study cellular lipid metabolism. As the lipidome contains numerous isomeric and isobaric species resulting in a significant overlap between different lipid classes, cutting-edge analytical technology is necessary for a comprehensive analysis of lipid metabolism. Just recently, differential mobility spectrometry (DMS) has evolved as such a technology, helping to overcome several analytical challenges. We here set out to apply DMS and the Lipidyzer™ platform to obtain a comprehensive overview of leukocyte-related lipid metabolism in the resting and activated states. First, we tested the linearity and repeatability of the platform by using HL60 cells. We obtained good linearities for most of the thirteen analyzed lipid classes (correlation coefficient > 0.95), and good repeatability (%CV < 15). By comparing the lipidome of neutrophils (PMNs), monocytes (CD14+), and lymphocytes (CD4+), we shed light on leukocyte-specific lipid patterns as well as lipidomic changes occurring through differential stimulation. For example, at the resting state, PMNs proved to contain higher amounts of triacylglycerides compared to CD4+ and CD14+ cells. On the other hand, CD4+ and CD14+ cells contained higher levels of phospholipids and ceramides. Upon stimulation, diacylglycerides, hexosylceramides, phosphatidylcholines, phosphoethanolamines, and lysophosphoethanolamines were upregulated in CD4+ cells and PMNs, whereas CD14+ cells did not show significant changes. By exploring the fatty acid content of the significantly upregulated lipid classes, we mainly found increased concentrations of very long and polyunsaturated fatty acids. Our results indicate the usefulness of the Lipidyzer™ platform for studying cellular lipid metabolism. Its application allowed us to explore the lipidome of leukocytes. Graphical abstract.
    Keywords:  CD14+; CD4+; IPA extraction; Lipidomics; Lipidyzer™; Neutrophils
    DOI:  https://doi.org/10.1007/s00216-020-02460-8
  5. Methods Mol Biol. 2020 ;2129 259-268
    Mass Spectrometry for Biomarkers Discovery in Esophageal Squamous Cell Carcinoma.
    Farhadul Islam, Vinod Gopalan, Alfred K Lam.
      Mass spectrometry-based proteomics analysis could categorize proteins and study their interactions in large scale in human cancers. By this method, many proteins are upregulated or downregulated in esophageal squamous cell carcinoma (ESCC) when compared to nonneoplastic esophageal mucosae. The method can also be used to identify novel, effective biomarkers for early diagnosis or predict prognosis of patients with ESCC. These changes are associated with different clinical and pathological parameters. Different biological matrices such as pathological tissue, body fluids, and cancer cell lines-based proteomics have widely been used. Herein, we described cell line-based label-free shotgun proteomics (in-solution tryptic digestion) to identify the protein biomarkers differently expressed in ESCC.
    Keywords:  Biomarkers; Cancer; ESCC; Label-free proteomics; Shotgun proteomics
    DOI:  https://doi.org/10.1007/978-1-0716-0377-2_19
  6. Ann Transl Med. 2019 Dec;7(23): 781
    Integrated metabolomics and lipidomics profiling of hippocampus reveal metabolite biomarkers in a rat model of chronic unpredictable mild stress-induced depression.
    Chunmei Geng, Yi Qiao, Yujin Guo, Wenxiu Han, Bin Wu, Changshui Wang, Jun Zhang, Dan Chen, Mengqi Yang, Pei Jiang.
       Background: Prolonged exposure to stress triggers depression, threatening human health. Thus, to thoroughly understand the underlying pathophysiologic mechanism of chronic unpredictable mild stress (CUMS)-induced depression is urgently needed. Ultra-high-performance liquid chromatography-mass spectroscopy (UPLC-MS)-based lipidomic and metabolomic approaches has been used for discovering metabolite biomarkers to develop new diagnostic and therapeutic means. Thus, our study aimed to conduct integrated metabolomics and lipidomics to identify metabolites and lipids biomarkers in the hippocampus in rat models of CUMS-induced depression.
    Methods: Twelve eight-week-old male Sprague-Dawley rats (weight 210±30 g) were randomly distributed to one of the following two groups (n=6): control or CUMS. Established UPLC-MS-based lipidomic and metabolomic approaches were used to determine the metabolites and lipids in the hippocampus of rats. SICMA-P and GraphPad software were performed to discover potential metabolites and lipids biomarkers in the hippocampus of rats between the two groups.
    Results: A total of 35 potential metabolites and 171 lipids were identified and found to be mainly related to amino acid and lipid metabolism. These metabolites were involved in different metabolic pathways and connected to each other, which might participate in the occurrence and development of depression.
    Conclusions: Our findings underlined the metabolites, lipids and metabolic pathways that were changed in the hippocampus in CUMS compared to the controls, providing novel insights in the metabolism in the hippocampus of rats and revealing the new lipid-related targets.
    Keywords:  Chronic unpredictable mild stress (CUMS); depression; lipidomics; metabolomics; ultra-high-performance liquid chromatography-mass spectroscopy (UPLC-MS)
    DOI:  https://doi.org/10.21037/atm.2019.11.21
  7. Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Feb 08. pii: S1388-1981(20)30048-2. [Epub ahead of print] 158656
    Automated untargeted stable isotope assisted lipidomics of liver cells on high glucose shows alteration of sphingolipid kinetics.
    Davide Noto, Francesca Di Gaudio, Ida Grazia Altieri, Angelo Baldassare Cefalù, Sergio Indelicato, Francesca Fayer, Rossella Spina, Chiara Scrimali, Antonina Giammanco, Alessandro Mattina, Serena Indelicato, Massimiliano Greco, David Bongiorno, Maurizio Averna.
      Untargeted lipidomics is a powerful tool to discover new biomarkers and to understand the physiology and pathology of lipids. The use of stable isotopes as tracers to investigate the kinetics of lipids is another tool able to supply dynamic information on lipid synthesis and catabolism. Coupling the two methodology is then very appealing in the study of lipid metabolism. The main issue to face is to perform thousands of calculations in order to obtain kinetic parameters starting from the MS raw data. An automated computerized routine able to do accomplish such task is presented in this paper. We analyzed the lipid kinetics of palmitic acid (PA) in hepatoma liver cells cultured in vitro in which insulin resistance has been induced by high glucose supplementation. The deuterated palmitate tracer (d5PA) was administered as a bolus and the cells were harvested daily for 48 h. 5dPA was incorporated into 326 monoisotopic compounds and in 84 of their [M + 1] isotopologues detected by high resolution orbitrap MS. The differences between the kinetics curves showed that at least four long chain triglycerides (TG) species incorporated more PA in glucose treated cells, while phosphocholines, sphingomyelins, mono- and di-glycerides and ceramides (Cer) incorporated less tracer under glucose treatment. Nevertheless, Cer amount was increased by glucose treatment. In conclusion we developed an automated powerful algorithm able to model simultaneously hundreds of kinetic curves obtained in a cell culture spiked with a stable isotope tracer, and to analyze the difference between the two different cell models.
    Keywords:  Automation; Cell models; High resolution mass spectrometry; Insulin resistance; Kinetics; Lipidomics
    DOI:  https://doi.org/10.1016/j.bbalip.2020.158656
  8. J Proteome Res. 2020 Feb 10.
    Kinobead/LC-MS Phosphokinome Profiling Enables Rapid Analyses of Kinase-Dependent Cell Signaling Networks.
    Martin Golkowski, Venkata Narayana Vidadala, Ho-Tak Lau, Anna Shoemaker, Masami Shimizu-Albergine, Joseph Beavo, Dustin J Maly, Shao-En Ong.
      Kinase-catalyzed protein phosphorylation is fundamental to eukaryotic signal transduction, regulating most cellular processes. Kinases are frequently dysregulated in cancer, inflammation and degenerative diseases, and because they can be inhibited with small molecules, they became important drug targets. Accordingly, analytical approaches that determine kinase activation states are critically important to understand kinase-dependent signal transduction, and to identify novel drug targets and predictive biomarkers. Multiplexed inhibitor beads (MIBs or kinobeads) efficiently enrich kinases from cell lysates for LC-MS analysis. When combined with phosphopeptide enrichment, kinobead/LC-MS can also quantify the phosphorylation state of kinases, which determines their activation state. However, an efficient kinobead/LC-MS kinase phospho-profiling protocol that allows routine analyses of cell lines and tissues has not yet been developed. Here, we present a facile workflow that quantifies the global phosphorylation state of kinases with unprecedented sensitivity. We also found that our kinobead/LC-MS protocol can measure changes in kinase complex composition and show how these changes can indicate kinase activity. We demonstrate the utility of our approach in specifying kinase signaling pathways that control the acute steroidogenic response in Leydig cells; this analysis establishes the first comprehensive framework for the post-translational control of steroid biosynthesis.
    DOI:  https://doi.org/10.1021/acs.jproteome.9b00742
  9. Cancer Discov. 2020 Feb 11. pii: CD-19-0297. [Epub ahead of print]
    Oncogenic Kras driven metabolic reprogramming in pancreas cancer cells utilizes cytokines from the tumor microenvironment.
    Prasenjit Dey, Jun Li, Jianhua Zhang, Surendra Chaurasiya, Anders Strom, Huamin Wang, Wen-Ting Liao, Frederick Cavallaro, Parker Denz, Vincent Bernard, Er-Yen Yen, Giannicola Genovese, Pat Gulhati, Jielin Liu, Deepavali Chakravarti, Pingna Deng, Tingxin Zhang, Federica Carbone, Qing Chang, Haoqiang Ying, Xiaoying Shang, Denise J Spring, Bidyut Ghosh, Nagireddy Putluri, Anirban Maitra, Y Alan Wang, Ronald A DePinho.
      A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic Kras in pro-tumorigenic signaling interactions between cancer cells and host cells. We show that Kras* drives cell autonomous expression of type I cytokine receptor complexes (IL2ry-IL4ra and IL2ry-IL13ra1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading TH2 cells in the microenvironment. Early neoplastic lesions show close proximity of Kras* cancer cells and TH2 cells producing IL4 and IL13. Activated IL2ry-IL4ra and IL2ry-IL13ra1 receptors signal primarily via Jak1-Stat6. Integrated transcriptomic, chromatin occupancy and metabolomic studies identified cMyc, as a direct target of activated Stat6, and that cMyc drives glycolysis. Thus paracrine signaling in the tumor microenvironment plays a key role in the Kras*-driven metabolic reprogramming of PDAC.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-0297
  10. Biochim Biophys Acta Rev Cancer. 2020 Feb 05. pii: S0304-419X(19)30206-9. [Epub ahead of print]1873(2): 188352
    Control of tumor angiogenesis and metastasis through modulation of cell redox state.
    José J Serrano, Belén Delgado, Miguel Ángel Medina.
      Redox reactions pervade all biology. The control of cellular redox state is essential for bioenergetics and for the proper functioning of many biological functions. This review traces a timeline of findings regarding the connections between redox and cancer. There is ample evidence of the involvement of cellular redox state on the different hallmarks of cancer. Evidence of the control of tumor angiogenesis and metastasis through modulation of cell redox state is reviewed and highlighted.
    Keywords:  Metastasis; Redox metabolism; Redox signaling; Tumor angiogenesis
    DOI:  https://doi.org/10.1016/j.bbcan.2020.188352
  11. Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Feb 10. pii: S1388-1981(20)30050-0. [Epub ahead of print] 158658
    Role of lipids in pathophysiology, diagnosis and therapy of hepatocellular carcinoma.
    Christa Buechler, Charalampos Aslanidis.
      Hepatocellular carcinoma (HCC) is an aggressive and widespread cancer. Patients with liver cirrhosis of different aetiologies are at a risk to develop HCC. It is important to know that in approximately 20% of cases primary liver tumors arise in a non-cirrhotic liver. Lipid metabolism is variable in patients with chronic liver diseases, and lipid metabolites involved therein do play a role in the development of HCC. Of note, lipid composition of carcinogenic tissues differs from non-affected liver tissues. High cholesterol and low ceramide levels in the tumors protect the cells from oxidative stress and apoptosis, and do also promote cell proliferation. So far, detailed characterization of the mechanisms by which lipids enable the development of HCC has received little attention. Evaluation of the complex roles of lipids in HCC is needed to better understand the pathophysiology of HCC, the later being of paramount importance for the development of urgently needed therapeutic interventions. Disturbed hepatic lipid homeostasis has systemic consequences and lipid species may emerge as promising biomarkers for early diagnosis of HCC. The challenge is to distinguish lipids specifically related to HCC from changes simply related to the underlying liver disease. This review article discusses aberrant lipid metabolism in patients with HCC.
    Keywords:  Ceramide; Cholesterol; Fatty acid; MELD score; Phospholipids
    DOI:  https://doi.org/10.1016/j.bbalip.2020.158658
  12. Cells. 2020 Feb 11. pii: E404. [Epub ahead of print]9(2):
    mTOR Regulation of Metabolism in Hematologic Malignancies.
    Simone Mirabilii, Maria Rosaria Ricciardi, Agostino Tafuri.
      Neoplastic cells rewire their metabolism, acquiring a selective advantage over normal cells and a protection from therapeutic agents. The mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase involved in a variety of cellular activities, including the control of metabolic processes. mTOR is hyperactivated in a large number of tumor types, and among them, in many hematologic malignancies. In this article, we summarized the evidence from the literature that describes a central role for mTOR in the acquisition of new metabolic phenotypes for different hematologic malignancies, in concert with other metabolic modulators (AMPK, HIF1α) and microenvironmental stimuli, and shows how these features can be targeted for therapeutic purposes.
    Keywords:  cell metabolism; hematologic malignancies; mTOR
    DOI:  https://doi.org/10.3390/cells9020404
  13. Cell Rep. 2020 Feb 11. pii: S2211-1247(20)30052-8. [Epub ahead of print]30(6): 1780-1797.e6
    Secreted Pyruvate Kinase M2 Promotes Lung Cancer Metastasis through Activating the Integrin Beta1/FAK Signaling Pathway.
    Caihong Wang, Shaosen Zhang, Jie Liu, Yang Tian, Boyuan Ma, Siran Xu, Yan Fu, Yongzhang Luo.
      Cancer cell-derived secretomes have been documented to play critical roles in cancer progression. Intriguingly, alternative extracellular roles of intracellular proteins are involved in various steps of tumor progression, which can offer strategies to fight cancer. Herein, we identify lung cancer progression-associated secretome signatures using mass spectrometry analysis. Among them, PKM2 is verified to be highly expressed and secreted in lung cancer cells and clinical samples. Functional analyses demonstrates that secreted PKM2 facilitates tumor metastasis. Furthermore, mass spectrometry analysis and functional validation identify integrin β1 as a receptor of secreted PKM2. Mechanistically, secreted PKM2 directly bound to integrin β1 and subsequently activated the FAK/SRC/ERK axis to promote tumor metastasis. Collectively, our findings suggest that PKM2 is a potential serum biomarker for diagnosing lung cancer and that targeting the secreted PKM2-integrin β1 axis can inhibit lung cancer development, which provides evidence of a potential therapeutic strategy in lung cancer.
    Keywords:  PKM2; integrin β1; lung cancer; metastasis; secretome
    DOI:  https://doi.org/10.1016/j.celrep.2020.01.037
  14. Cancer Discov. 2020 Feb 14.
    Energy Stress Inhibits Ferroptotic Cell Death via AMPK Activation.
      In response to glucose starvation, AMPK inhibited lipid peroxidation-associated ferroptosis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-023
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