bims-mascan Biomed News
on Mass spectrometry in cancer research
Issue of 2022‒04‒10
twelve papers selected by
Giovanny Rodriguez Blanco
University of Edinburgh

  1. Expert Rev Mol Diagn. 2022 Apr 08.
      INTRODUCTION: Adaptations of eukaryotic cells to environmental changes are important for their survival. However, under some circumstances, microenvironmental changes promote that eukaryotic cells utilize a metabolic signature resembling a unicellular organism named the Warburg effect. Most cancer cells share the Warburg effect displaying lactic fermentation and high glucose uptake. The Warburg effect also induces a metabolic rewiring stimulating glutamine consumption and lipid synthesis, also considered cancer hallmarks. Amino acid metabolism alteration due to the Warburg effect increases plasma levels of proline and branched-chain amino acids in several cancer types. Proline and lipids are probably used as electron transfer molecules in carcinogenic cells. In addition, branched-chain amino acids fuel the Krebs cycle, protein synthesis, and signaling in cancer cells.AREAS COVERED: This review covers how metabolomics studies describe changes in some metabolites and proteins associated with the Warburg effect and related metabolic pathways.
    EXPERT OPINION: In this review, we analyze the metabolic signature of the Warburg effect and related phenotypes and propose some Warburg effect-related metabolites and proteins (lactate, glucose uptake, glucose transporters, glutamine, branched-chain amino acids, proline, and some lipogenic enzymes) as promising cancer biomarkers.
    Keywords:  Biomarker; Warburg effect; cancer; diagnosis; metabolism; molecular prognosis
  2. Mol Cell. 2022 Mar 30. pii: S1097-2765(22)00260-X. [Epub ahead of print]
      Ferroptosis, a newly emerged form of regulated necrotic cell death, has been demonstrated to play an important role in multiple diseases including cancer, neurodegeneration, and ischemic organ injury. Mounting evidence also suggests its potential physiological function in tumor suppression and immunity. The execution of ferroptosis is driven by iron-dependent phospholipid peroxidation. As such, the metabolism of biological lipids regulates ferroptosis via controlling phospholipid peroxidation, as well as various other cellular processes relevant to phospholipid peroxidation. In this review, we provide a comprehensive analysis by focusing on how lipid metabolism impacts the initiation, propagation, and termination of phospholipid peroxidation; how multiple signal transduction pathways communicate with ferroptosis via modulating lipid metabolism; and how such intimate cross talk of ferroptosis with lipid metabolism and related signaling pathways can be exploited for the development of rational therapeutic strategies.
    Keywords:  cancer therapy; ferroptosis; lipid metabolism
  3. Subcell Biochem. 2022 ;98 15-40
      Macropinocytosis is an evolutionarily conserved endocytic pathway that mediates the nonselective acquisition of extracellular material via large endocytic vesicles known as macropinosomes. In addition to other functions, this uptake pathway supports cancer cell metabolism through the uptake of nutrients. Cells harboring oncogene or tumor suppressor mutations are known to display heightened macropinocytosis, which confers to the cancer cells the ability to survive and proliferate despite the nutrient-scarce conditions of the tumor microenvironment. Thus, macropinocytosis is associated with cancer malignancy. Macropinocytic uptake can be induced in cancer cells by different stress stimuli, acting as an adaptive mechanism for the cells to resist stresses in the tumor milieu. Here, we review the cellular stresses that are known to promote macropinocytosis, as well as the underlying molecular mechanisms that drive this process.
    Keywords:  Cancer malignancy; Cell metabolism; Macropinocytosis; Nutrient scarcity; Nutrient uptake; Stress stimuli
  4. Front Pharmacol. 2022 ;13 840440
      The hallmarks of cancer include dysregulated metabolism and immune evasion. As a basic way of metabolism, lipid metabolism is reprogrammed for the rapid energy and nutrient supply in the occurrence and development of tumors. Lipid metabolism alterations that occur in the tumor microenvironment (TME) affect the antitumor responses of immune cells and cause immune evasion. Therefore, targeting lipid metabolism in the TME for enhancing the antitumor effect of immune cells is a promising direction for cancer treatment. Cancer nanomedicine has great potential in regulating tumor metabolism and tumor immunity. This review summarizes the nanotechnology-based strategies for lipid metabolism regulation in the TME for enhanced anticancer immune responses.
    Keywords:  cancer nanomedicine; lipid metabolism; nanotechnology; tumor immunity; tumor metabolism; tumor microenvironment
  5. Metabolomics. 2022 Apr 09. 18(4): 24
      INTRODUCTION: The metabolomics quality assurance and quality control consortium (mQACC) is enabling the identification, development, prioritization, and promotion of suitable reference materials (RMs) to be used in quality assurance (QA) and quality control (QC) for untargeted metabolomics research.OBJECTIVES: This review aims to highlight current RMs, and methodologies used within untargeted metabolomics and lipidomics communities to ensure standardization of results obtained from data analysis, interpretation and cross-study, and cross-laboratory comparisons. The essence of the aims is also applicable to other 'omics areas that generate high dimensional data.
    RESULTS: The potential for game-changing biochemical discoveries through mass spectrometry-based (MS) untargeted metabolomics and lipidomics are predicated on the evolution of more confident qualitative (and eventually quantitative) results from research laboratories. RMs are thus critical QC tools to be able to assure standardization, comparability, repeatability and reproducibility for untargeted data analysis, interpretation, to compare data within and across studies and across multiple laboratories. Standard operating procedures (SOPs) that promote, describe and exemplify the use of RMs will also improve QC for the metabolomics and lipidomics communities.
    CONCLUSIONS: The application of RMs described in this review may significantly improve data quality to support metabolomics and lipidomics research. The continued development and deployment of new RMs, together with interlaboratory studies and educational outreach and training, will further promote sound QA practices in the community.
    Keywords:  Certified reference materials; Internal standards; Lipidomics; Mass spectrometry; Metabolomics; Metabolomics quality assurance and quality control consortium (mQACC); Reference materials; Untargeted analysis
  6. Front Psychiatry. 2022 ;13 802710
      Lipidomics has become a pivotal tool in biomarker discovery for the diagnosis of psychiatric illnesses. However, the composition and quantitative analysis of peripheral lipids in female patients with bipolar disorder (BD) have been poorly addressed. In this study, plasma samples from 24 female patients with BD and 30 healthy controls (HCs) were analyzed by comprehensive lipid profiling and quantitative validation based on liquid chromatography-mass spectrometry. Clinical characteristics and a correlation between the level of lipid molecules and clinical symptoms were also observed. We found that the quantitative alterations in several lipid classes, including acylcarnitine, lysophosphatidylethanolamine, GM2, sphingomyelin, GD2, triglyceride, monogalactosyldiacylglycerol, phosphatidylinositol phosphate, phosphatidylinositol 4,5-bisphosphate, phosphatidylethanolamine, phosphatidylserine, and lysophosphatidylinositol, were remarkably upregulated or downregulated in patients with BD and were positively or negatively correlated with the severity of psychotic, affective, or mania symptoms. Meanwhile, the composition of different carbon chain lengths and degrees of fatty acid saturation for these lipid classes in BD were also different from those of HCs. Moreover, 55 lipid molecules with significant differences and correlations with the clinical parameters were observed. Finally, a plasma biomarker set comprising nine lipids was identified, and an area under the curve of 0.994 was obtained between patients with BD and the HCs. In conclusion, this study provides a further understanding of abnormal lipid metabolism in the plasma and suggests that specific lipid species can be used as complementary biomarkers for the diagnosis of BD in women.
    Keywords:  bipolar disorder; healthy controls; lipidomics; plasma; women
  7. Mol Metab. 2022 Mar 30. pii: S2212-8778(22)00047-3. [Epub ahead of print] 101478
      OBJECTIVE: Profound metabolic alterations characterize cancer development and, beyond glucose addiction, amino acid (AA) dependency is now recognized as a hallmark of tumour growth. Therefore, targeting the metabolic addiction of tumours by reprogramming their substrate utilization is an attractive therapeutic strategy. We hypothesized that a dietary approach targeted to stimulate oxidative metabolism could reverse the metabolic inflexibility of tumours and represent a proper adjuvant therapy.METHODS: We measured tumour development in xenografted mice fed with a designer, casein-deprived diet enriched in free essential amino acids (EAAs; SFA-EAA diet), or two control isocaloric, isolipidic, and isonitrogenous diets, identical to the SFA-EAA diet except for casein presence (SFA diet), or casein replacement by the free AA mixture designed on the AA profile of casein (SFA-CAA diet). Moreover, we investigated the metabolic, biochemical, and molecular effects of two mixtures that reproduce the AA composition of the SFA-EAA diet (i.e., EAAm) and SFA-CAA diet (i.e., CAAm) in diverse cancer and non-cancer cells.
    RESULTS: The SFA-EAA diet reduced tumour growth in vivo, promoted endoplasmic reticulum (ER) stress, and inhibited mechanistic/mammalian target of rapamycin (mTOR) activity in the tumours. Accordingly, in culture, the EAAm, but not the CAAm, activated apoptotic cell death in cancer cells without affecting the survival and proliferation of non-cancer cells. The EAAm increased branched-chain amino acid (BCAA) oxidation and decreased glycolysis, ATP levels, redox potential, and intracellular content of selective non-essential amino acids (NEAA) in cancer cells. The EAAm-induced NEAA starvation activated the GCN2-ATF4 stress pathway, leading to ER stress, mTOR inactivation, and apoptosis in cancer cells, unlike non-cancer cells.
    CONCLUSION: Together, these results confirm the efficacy of specific EAA mixtures in promoting cancer cells' death and suggest that manipulation of dietary EAA content and profile could be a valuable support to the standard chemotherapy for specific cancers.
    Keywords:  Branched-chain amino acids; Cancer metabolism; Essential amino acids; Glycolysis; Mechanistic/mammalian target of rapamycin; Mitochondria
  8. Curr Protoc. 2022 Apr;2(4): e413
      Ferroptosis is iron-dependent, lipid peroxidation-driven, regulated cell death that is triggered when cellular glutathione peroxidase 4 (GPX4)-mediated cellular defense is insufficient to prevent pathologic accumulation of toxic lipid peroxides. Ferroptosis is implicated in various human pathologies, including neurodegeneration, chemotherapy-resistant cancers, ischemia-reperfusion injury, and acute and chronic kidney diseases. Despite the fact that the ferroptotic process has been rigorously interrogated in multiple preclinical models, the lack of specific and readily available biomarkers to detect ferroptosis in vivo in mouse models makes it challenging to delineate its contribution to key pathologic events in vivo. Critical steps to practically evaluate ferroptosis include, but are not limited to, detecting increased cell death and pathologic accumulation of toxic lipid peroxides and testing augmentation of observed pathologic events by genetic inhibition of the glutathione-GPX4 axis or mitigation of the pathologic process by ferroptosis inhibitors. Here, we describe methods to evaluate these key features of the ferroptotic process in mice in vivo. Specifically, we describe methods to detect toxic lipid peroxides (4-hydroxynonenal) and cell death (based on terminal deoxynucleotidyl transferase dUTP nick end labeling staining) as well as a protocol to pharmacologically inhibit ferroptotic stress using liproxstatin-1. These protocols provide tools for understanding the ferroptotic process in mouse genetic or disease models. © 2022 Wiley Periodicals LLC. Basic Protocol 1: How to use liproxstatin-1 Basic Protocol 2: How to evaluate ferroptosis in mouse kidneys.
    Keywords:  4-HNE; 4-hydroxynonenal; ferroptosis; liproxstatin-1; mouse disease models
  9. Front Cell Dev Biol. 2022 ;10 849625
      Ubiquitination and SUMOylation, which are posttranslational modifications, play prominent roles in regulating both protein expression and function in cells, as well as various cellular signal transduction pathways. Metabolic reprogramming often occurs in various diseases, especially cancer, which has become a new entry point for understanding cancer mechanisms and developing treatment methods. Ubiquitination or SUMOylation of protein substrates determines the fate of modified proteins. Through accurate and timely degradation and stabilization of the substrate, ubiquitination and SUMOylation widely control various crucial pathways and different proteins involved in cancer metabolic reprogramming. An understanding of the regulatory mechanisms of ubiquitination and SUMOylation of cell proteins may help us elucidate the molecular mechanism underlying cancer development and provide an important theory for new treatments. In this review, we summarize the processes of ubiquitination and SUMOylation and discuss how ubiquitination and SUMOylation affect cancer metabolism by regulating the key enzymes in the metabolic pathway, including glucose, lipid and amino acid metabolism, to finally reshape cancer metabolism.
    Keywords:  SUMOylation; cancer; glucose metabolism; lipid metabolism; metabolic reprogramming; ubiquitination
  10. Expert Rev Proteomics. 2022 Apr 07.
      INTRODUCTION: The comprehensive collection of peptides presented by Major Histocompatibility Complex (MHC) molecules on the cell surface is collectively known as the immunopeptidome. The analysis and interpretation of such data sets holds great promise for furthering our understanding of basic immunology and adaptive immune activation and regulation, and for direct rational discovery of T cell antigens and the design of T-cell based therapeutics and vaccines. These applications are however challenged by the complex nature of immunopeptidome data.AREAS COVERED: Here, we describe the benefits and shortcomings of applying liquid chromatography-tandem mass spectrometry (MS) to obtain large scale immunopeptidome data sets and illustrate how the accurate analysis and optimal interpretation of such data is reliant on the availability of refined and highly optimized machine learning approaches.
    EXPERT OPINION: Further we demonstrate how the accuracy of immunoinformatics prediction methods within the field of MHC antigen presentation has benefited greatly from the availability of MS-immunopeptidomics data, and exemplify how optimal antigen discovery is best performed in a synergistic combination of MS experiments and such in silico models trained on large scale immunopeptidomics data.
    Keywords:  HLA; Immunopeptidomics; Machine learning; Mass spectrometry; T cell epitopes
  11. Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Apr 02. pii: S1388-1981(22)00047-6. [Epub ahead of print] 159157
      Adenosine triphosphate-binding cassette transporter subfamily A member 7 (ABCA7) performs incompletely understood biochemical functions that affect pathogenesis of Alzheimer's disease. ABCA7 is most similar in primary structure to ABCA1, the protein that mediates cell lipid efflux and formation of high-density lipoprotein (HDL). Lipid metabolic labeling/tracer efflux assays were employed to investigate lipid efflux in BHK-ABCA7(low expression), BHK-ABCA7(high expression) and BHK-ABCA1 cells. Shotgun lipid mass spectrometry was used to determine lipid composition of HDL synthesized by BHK-ABCA7 and BHK-ABCA1 cells. BHK-ABCA7(low) cells exhibited significant efflux only of choline-phospholipid and phosphatidylinositol. BHK-ABCA7(high) cells had significant cholesterol and choline-phospholipid efflux to apolipoprotein (apo) A-I, apo E, the 18A peptide, HDL, plasma and cerebrospinal fluid and significant efflux of sphingosine-lipid, serine-lipid (which is composed of phosphatidylserine and phosphatidylethanolamine in BHK cells) and phosphatidylinositol to apo A-I. In efflux assays to apo A-I, after adjustment to choline-phospholipid, ABCA7-mediated efflux removed ~4 times more serine-lipid and phosphatidylinositol than ABCA1-mediated efflux, while ABCA1-mediated efflux removed ~3 times more cholesterol than ABCA7-mediated efflux. Shotgun lipidomic analysis revealed that ABCA7-HDL had ~20 mol% less phosphatidylcholine and 3-5 times more serine-lipid and phosphatidylinositol than ABCA1-HDL, while ABCA1-HDL contained only ~6 mol% (or ~1.1 times) more cholesterol than ABCA7-HDL. The discrepancy between the tracer efflux assays and shotgun lipidomics with respect to cholesterol may be explained by an underestimate of ABCA7-mediated cholesterol efflux in the former approach. Overall, these results suggest that ABCA7 lacks specificity for phosphatidylcholine and releases significantly but not dramatically less cholesterol in comparison with ABCA1.
    Keywords:  ABC transporters; Apolipoprotein; Cholesterol metabolism; HDL formation; Lipid efflux; Phospholipid metabolism
  12. Curr Med Chem. 2022 Apr 01.
      Mitochondria are the main energy factory in living cells. To rapidly proliferate and metastasize, neoplastic cells increase their energy requirements. Thus, mitochondria become one of the most important organelles for them. Indeed, much research shows the interplay between cancer chemoresistance and altered mitochondrial function. In this review we focus on the differences in energy metabolism between cancer and normal cells, to better understand their resistance and how to develop drugs targeting energy metabolism and nucleotide synthesis. One of the differences between cancer and normal cells is the higher nicotinamide adenine dinucleotide (NAD+) level, a cofactor for the tricarboxylic acid cycle (TCA), which enhances their proliferation and helps cancer cells survive under hypoxic conditions. An important change is a metabolic switch, called the Warburg effect. This effect is based on the change of energy harvesting from oxygen-dependent transformation to oxidative phosphorylation (OXPHOS), adapt them to the tumor environment. Another mechanism is the high expression of one carbon (1C) metabolism enzymes. Again, this allows cancer cells to increase proliferation by producing precursors for the synthesis of nucleotides and amino acids. We reviewed drugs in clinical practice and in development targeting NAD+, OXPHOS, and 1C metabolism. Combinations of novel drugs with conventional antineoplastic agents may prove to be a promising new way of anticancer treatment.
    Keywords:  1C Metabolism; Cancer; Mitochondria; NAD+; Oxidative Phosphorylation (OXPHOS); Resistance