bims-mascan Biomed News
on Mass spectrometry in cancer research
Issue of 2022‒05‒01
25 papers selected by
Giovanny Rodriguez Blanco
University of Edinburgh

  1. Methods Mol Biol. 2022 ;2504 157-173
      Lipidomics is an omics approach to comprehensively study lipid profiles in biological samples, such as plasma, serum, urine, and tissue specimens. Moreover, lipidomic analyses are useful for identifying novel lipid biomarkers, especially for various metabolic and malignant diseases in humans. Extracellular vesicles (EVs) are lipid bilayer-encapsulated nanoparticles secreted from various cells into the extracellular space. In particular, circulating EVs in the blood stream have attracted considerable research interest as they are considered the fingerprint of the cells from which they are secreted and are a promising source for less-invasive biomarker screening. Here, we describe the entire workflow for the lipidomic analysis of circulating EVs, including the methods for their purification from human plasma and serum, liquid chromatography coupled with high-resolution mass spectrometry-based lipid measurement, and data analyses for profiling EV lipids. Using this methodological workflow, over 260 lipid molecules belonging to the glycerophospholipid and sphingolipid groups can be detected.
    Keywords:  Extracellular vesicles; Lipid biomarkers; Lipidomics; Liquid biopsy; Liquid chromatography coupled with high-resolution mass spectrometry
  2. J Drug Target. 2022 Apr 28. 1-28
      Alterations in cellular energy metabolism, including glycolysis, glutamine and lipid metabolism that affects ferroptosis in the tumor microenvironment (TME), play a critical role in the development and progression of colorectal cancer (CRC) and offer evolutionary advantages to tumor cells and even enhance their aggressive phenotype. This review summarizes the findings on the dysregulated energy metabolism pathways, including lipid and fatty acid metabolism especially for regulating the ferroptosis in TME. Moreover, the cellular energy metabolism and tumor ferroptosis to be regulated by small molecule compounds, which targeting the different aspects of metabolic pathways of energy production as well as metabolic enzymes that connect with the tumor cell growth and ferroptosis in CRC are also discussed. In this review, we will provide a comprehensive summary on small molecule compounds regulatory function of different energy metabolic routes on ferroptosis in tumor cells and discuss those metabolic vulnerabilities for the development of potential ferroptosis-based tumor therapies for colorectal cancer.
    Keywords:  Colorectal cancers; energy metabolism; small molecule compounds; tumor ferroptosis
  3. Methods Mol Biol. 2022 ;2490 157-177
      In this methods chapter, we describe the use of isobaric tags for relative and absolute quantification (iTRAQ) for the differential expression analysis of global proteins between embryonic stem cell samples. This protocol describes how proteins are collected from cell culture, digested and prepared so that peptides are labeled with these isobaric tags. Labeled digests are pooled, fractionated offline, and quantified using liquid chromatography-mass spectrometry (LC-MS). This offline fractionation allows for a greater separation and thus increased identification/quantification of peptides. This combined method enables large-scale, deep penetration into the proteome of embryonic stem cells. During quantification, the relative intensities of label-derived reporter ions represent the relative amount of peptide in each sample. Using search algorithms that integrate the generated data for the identified and quantified peptides allows the relative quantification of proteins in the samples. The isobaric tags can be used in a 4 or 8 multiplexed manner; however, using an 8-plex experimental setup allows for the simultaneous analysis of biological and technical replicates within the same mass spectrometry run, thus minimizing experimental variation and increasing the confidence in any identified expression differences.
    Keywords:  ESCs; Embryonic stem cells; Global proteomics; LC-MS/MS; Liquid Chromatography; Mass spectrometry; Proteomics; iPSCs; iTRAQ
  4. Methods Mol Biol. 2022 ;2484 3-12
      Metabolite profiling aiming at quantifying the metabolome of flowers is emerging as a suitable tool to understand the metabolic complexity of these reproductive organs and the associations between primary and secondary metabolites which characterize them. This chapter provides a general method for the combined analyses of primary and secondary metabolites via gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography-mass spectrometry (LC-MS) of flower samples. We describe the preparatory steps, the procedure of metabolites' extraction and finally provide examples of data representation. The method described here can be applied to the analysis of metabolomes of entire flowers, as well as specific flower organs.
    Keywords:  Flower; GC-MS; LC-MS; Primary metabolites; Secondary metabolites
  5. Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00004-1. [Epub ahead of print]367 65-100
      Macrophages functionally adapt to a diverse set of signals, a process that is critical for their role in maintaining or restoring tissue homeostasis. This process extends to cancer, where macrophages respond to a series of inflammatory and metabolic cues that direct a maladaptive healing response. Tumor-associated macrophages (TAMs) have altered glucose, amino acid, and lipid metabolic profiles, and interfering with this metabolic shift can blunt the ability of macrophages to promote tumor growth, metastasis, and the creation of an immunosuppressive microenvironment. Here we will review changes in metabolites and metabolic pathways in TAMs and link these with the phenotypic and functional properties of the cells. We will also discuss current strategies targeting TAM metabolism as a therapeutic intervention in cancer.
    Keywords:  Immunometabolism; Metabolic reprogramming; Metabolism; Tumor microenvironment; Tumor-associated macrophages
  6. Trends Cancer. 2022 Apr 22. pii: S2405-8033(22)00089-9. [Epub ahead of print]
      Tumor cell-intrinsic metabolic features can affect the cancer-immunity dialogue. In a recent paper published in Cancer Cell, Liao et al. demonstrate that IFNγ produced by T cells, together with arachidonic acid, can induce acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis, correlating with increased immunosurveillance and response to checkpoint blockade.
    Keywords:  PARP; immunogenic cell death; immunotherapy
  7. Cell Rep Methods. 2021 Jun 21. 1(2): 100003
      Mass-spectrometry-based proteomics enables quantitative analysis of thousands of human proteins. However, experimental and computational challenges restrict progress in the field. This review summarizes the recent flurry of machine-learning strategies using artificial deep neural networks (or "deep learning") that have started to break barriers and accelerate progress in the field of shotgun proteomics. Deep learning now accurately predicts physicochemical properties of peptides from their sequence, including tandem mass spectra and retention time. Furthermore, deep learning methods exist for nearly every aspect of the modern proteomics workflow, enabling improved feature selection, peptide identification, and protein inference.
    Keywords:  MS/MS; bioinformatics; deep learning; mass spectrometry; neural networks; peptides; proteomics; retention time
  8. Mol Cell Proteomics. 2022 Apr 21. pii: S1535-9476(22)00046-9. [Epub ahead of print] 100238
      Isobaric stable isotope labeling techniques such as tandem mass tags (TMT) have become popular in proteomics because they enable the relative quantification of proteins with high precision from up to 18 samples in a single experiment. While missing values in peptide quantification are rare in a single TMT experiment, they rapidly increase when combining multiple TMT experiments. As the field moves towards analyzing ever higher numbers of samples, tools that reduce missing values also become more important for analyzing TMT datasets. To this end, we developed SIMSI-Transfer (Similarity-based Isobaric MS2 Identification Transfer), a software tool that extends our previously developed software MaRaCluster by clustering similar tandem mass spectra (MS2) from multiple TMT experiments. SIMSI-Transfer is based on the assumption that similarity-clustered MS2 spectra represent the same peptide. Therefore, peptide identifications made by database searching in one TMT batch can be transferred to another TMT batch in which the same peptide was fragmented but not identified. To assess the validity of this approach, we tested SIMSI-Transfer on masked search engine identification results and recovered >80% of the masked identifications while controlling errors in the transfer procedure to below 1% FDR. Applying SIMSI-Transfer to six published full proteome and phosphoproteome data sets from the CPTAC (Clinical Proteomic Tumor Analysis Consortium) led to an increase of 26-45% of identified MS2 spectra with TMT quantifications. This significantly decreased the number of missing values across batches and, in turn, increased the number of peptides and proteins identified in all TMT batches by 43-56% and 13-16%, respectively.
  9. JHEP Rep. 2022 Jun;4(6): 100479
      Lipids are a complex and diverse group of molecules with crucial roles in many physiological processes, as well as in the onset, progression, and maintenance of cancers. Fatty acids and cholesterol are the building blocks of lipids, orchestrating these crucial metabolic processes. In the liver, lipid alterations are prevalent as a cause and consequence of chronic hepatitis B and C virus infections, alcoholic hepatitis, and non-alcoholic fatty liver disease and steatohepatitis. Recent developments in lipidomics have also revealed that dynamic changes in triacylglycerols, phospholipids, sphingolipids, ceramides, fatty acids, and cholesterol are involved in the development and progression of primary liver cancer. Accordingly, the transcriptional landscape of lipid metabolism suggests a carcinogenic role of increasing fatty acids and sterol synthesis. However, limited mechanistic insights into the complex nature of the hepatic lipidome have so far hindered the development of effective therapies.
    Keywords:  ACC, acetyl-CoA carboxylase; ACLY, ATP citrate lyase; ALD, alcohol-related liver disease; BAs, bile acids; CCA, cholangiocarcinoma; CPT, carnitine palmitoyltransferase; Cer, ceramide(s); DNL, de novo lipogenesis; ELOV1-6, elongation of very-long-chain fatty acids; FA, fatty acid; FABP, fatty acid-binding protein; FADS2, fatty acid desaturase 2; FAO, fatty acid oxidation; FASN, fatty acid synthase; FXR, farnesoid X receptor; HCC, hepatocellular carcinoma; HMGCR, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; HSCs, hepatic stellate cells; LA, linoleic acid; LPC, lysophosphatidylcholine; LXR, liver X receptor; MUFA, monounsaturated fatty acid; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; Non-alcoholic fatty liver disease; PC, phosphatidylcholine; PPARs, peroxisome proliferator-activated receptors; PSC, primary sclerosing cholangitis; PUFA, polyunsaturated fatty acid; S1P, sphingosine-1-phosphate; SCD, stearoyl-CoA desaturase; SE, sterol esters; SFA, saturated fatty acid; SM, sphingomyelin; SREBP, sterol regulatory element-binding protein; TERT, telomerase reverse transcriptase; TG, triglycerides; TLR, Toll-like receptor; cholangiocarcinoma; hepatocellular carcinoma; lipidomics; metabolomics
  10. Autophagy. 2022 Apr 26. 1-2
      Cancer cells metabolize glutamine mostly through glutaminolysis, a metabolic pathway that activates MTORC1. The AMPK-MTORC1 signaling axis is a key regulator of cell growth and proliferation. Our recent investigation identified that the connection between glutamine and AMPK is not restricted to glutaminolysis. Rather, we demonstrated the crucial role of ASNS (asparagine synthetase (glutamine-hydrolyzing)) and the GABA shunt for the metabolic control of the AMPK-MTORC1 axis during glutamine sufficiency. Our results elucidated a metabolic network by which glutamine metabolism regulates the MTORC1-macroautophagy/autophagy pathway through two independent branches involving glutaminolysis and ASNS-GABA shunt.
    Keywords:  ASNS; GABA-shunt; MTORC1; glutamine; glutamoptosis
  11. Anal Chim Acta. 2022 May 08. pii: S0003-2670(22)00332-4. [Epub ahead of print]1206 339761
      Irinotecan (Iri) is a key drug to treat metastatic colorectal cancer, but its clinical activity is often limited by de novo and acquired drug resistance. Studying the underlying mechanisms of drug resistance is necessary for developing novel therapeutic strategies. In this study, we used both regular and irinotecan-resistant (Iri-resistant) colorectal cell lines as models, and performed single cell mass spectrometry (SCMS) metabolomics studies combined with analyses from cytotoxicity assay, western blot, flow cytometry, quantitative real-time polymerase chain reaction (qPCR), and reactive oxygen species (ROS). Our SCMS results indicate that Iri-resistant cancer cells possess higher levels of unsaturated lipids compared with the regular cancer cells. In addition, multiple protein biomarkers and their corresponding mRNAs of colon cancer stem cells are overexpressed in Iri-resistance cells. Particularly, stearoyl-CoA desaturase 1 (SCD1) is upregulated with the development of drug resistance in Iri-resistant cells, whereas inhibiting the activity of SCD1 efficiently increase their sensitivity to Iri treatment. In addition, we demonstrated that SCD1 directly regulates the expression of ALDH1A1, which contributes to the cancer stemness and ROS level in Iri-resistant cell lines.
  12. STAR Protoc. 2022 Jun 17. 3(2): 101302
      We describe here a user-friendly analysis protocol for semi-targeted polar metabolomics in human muscle biopsies using Zwitterionic Hydrophilic Interaction Liquid Chromatography and high-resolution full-scan mass spectrometry. Previously, this protocol has been used for Caenorhabditis elegans. Here we show that it can be successfully applied to human muscle biopsies with minor adjustments. Summarized instructions for other matrices are also provided. As peak integration in metabolomics can be challenging, we provide expected retention times and extensive peak descriptions to aid this process. For complete details on the use and execution of this protocol, please refer to Molenaars et al. (2021).
    Keywords:  Health Sciences; Mass Spectrometry; Metabolism; Metabolomics
  13. Pharmacol Res Perspect. 2022 Jun;10(3): e00944
      Monocarboxylate transporter 6 (MCT6; SLC16A5) is an orphan transporter protein with expression in multiple tissues. The endogenous function of MCT6 related to human health and disease remains unknown. Our previous transcriptomic and proteomic analyses in Mct6 knockout (KO) mice suggested that MCT6 may play a role in lipid and glucose homeostasis, but additional evidence is required. Thus, the objective of this study was to further explore the impact of MCT6 on metabolic function using untargeted metabolomic analysis in Mct6 KO mice. The plasma from male and female mice and livers from male mice were submitted for global metabolomics analysis to assess the relative changes in endogenous small molecules across the liver and systemic circulation associated with absence of Mct6. More than 782 compounds were detected with 101 and 51 metabolites significantly changed in plasma of male and female mice, respectively, and 100 metabolites significantly changed in the livers of male mice (p < .05). Significant perturbations in lipid metabolism were annotated in the plasma and liver metabolome, with additional alterations in the amino acid metabolism pathway in plasma samples from male and female mice. Elevated lipid diacylglycerol and altered fatty acid metabolite concentrations were found in liver and plasma samples of male Mct6 KO mice. Significant reduction of N-terminal acetylated amino acids was found in plasma samples of male and female Mct6 KO mice. In summary, the present study confirmed the significant role of MCT6 in lipid and amino acid homeostasis, suggesting its contribution in metabolic diseases.
    Keywords:  MCT6; PPAR-alpha; SLC16A5; amino acid homeostasis; lipid metabolism; metabolomics
  14. Nat Chem Biol. 2022 May;18(5): 441-450
      Metabolic reprogramming is observed across all cancer types. Indeed, the success of many classic chemotherapies stems from their targeting of cancer metabolism. Contemporary research in this area has refined our understanding of tumor-specific metabolic mechanisms and has revealed strategies for exploiting these vulnerabilities selectively. Based on this growing understanding, new small-molecule tools and drugs have been developed to study and target tumor metabolism. Here, we highlight allosteric modulation of metabolic enzymes as an attractive mechanism of action for small molecules that target metabolic enzymes. We then discuss the mechanistic insights garnered from their application in cancer studies and highlight the achievements of this approach in targeting cancer metabolism. Finally, we discuss technological advances in drug discovery for allosteric modulators of enzyme activity.
  15. Anal Chem. 2022 Apr 28.
      Sialic acids have diverse biological roles, ranging from promoting up to preventing protein and cellular recognition in health and disease. The various functions of these monosaccharides are owed, in part, to linkage variants, and as a result, linkage-specific analysis of sialic acids is an important aspect of glycomic studies. This has been addressed by derivatization strategies using matrix-assisted laser desorption/ionization mass spectrometry (MS) or sialidase digestion arrays followed by liquid chromatography (LC)-MS. Despite this, these approaches are unable to simultaneously provide unambiguous assignment of sialic acid linkages and assess further isomeric glycan features within a single measurement. Thus, for the first time, we present the combination of procainamide fluorescent labeling with sialic acid linkage-specific derivatization via ethyl esterification and amidation for the analysis of released plasma N-glycans using reversed-phase (RP)LC-fluorescence detection (FD)-MS. As a result, α2,3- and α2,6-sialylated N-glycans, with the same mass prior to derivatization, are differentiated based on retention time, precursor mass, and fragmentation spectra, and additional sialylated isomers were also separated. Furthermore, improved glycan coverage and protocol precision were found via the novel application using a combined FD-MS quantification approach. Overall, this platform achieved unambiguous assignment of N-glycan sialic acid linkages within a single RPLC-FD-MS measurement, and by improving their retention on RPLC, this technique can be used for future investigations of released N-glycans as an additional or orthogonal method to current analytical approaches.
  16. Talanta. 2022 Apr 12. pii: S0039-9140(22)00271-5. [Epub ahead of print]245 123475
      Sphingolipids (SPLs) are bioactive lipids that manifest structural diversity and complexity in eukaryotes. However, the distributions and functions of these molecules in mammalian tissues/cells have not been systematically investigated. Herein, we integrated shotgun lipidomics with targeted LC-MRM/MS approach to comprehensively analyze SPL species in various biological samples with high accuracy. Preliminarily, 1311 SPL molecules were identified in 18 kinds of mammalian samples, including 3 groups of human sera, 10 mouse tissues and 5 cell lines via 26 sphingoid long-chain bases scanning. The sphingolipidome compositions and distributions were systematically characterized and distinct qualitative and quantitative profiles were clearly exhibited in various samples, indicating unique biological functions of the sphingolipidomes. Next, targeted SPLs analysis by LC-MRM/MS with critical criteria monitoring two characteristic fragments of one precursor was applied to human serum samples from 24 coronary artery disease (CAD) patients and 12 healthy controls, which successfully quantified 170 SPL molecules. Ten novel SPL molecules were discovered as a potential diagnostic panel for CAD patients via multivariate exploratory receiver operating characteristic curve-based biomarker analysis. The diagnostic panel with the 10 SPL molecules achieved 97.2% accuracy, with a favorable auxiliary diagnostic value (AUC = 1.000), for the detection of CAD. These results clearly support the sphingolipidomic approach in application to discovering disease biomarker panel as well as deep investigation of biological functions of complex SPLs in mammalian samples.
    Keywords:  Coronary artery disease; Diagnostic panel; LC-MRM/MS approach; Shotgun lipidomics; Sphingolipids
  17. Curr Res Transl Med. 2022 Apr 26. pii: S2452-3186(22)00014-9. [Epub ahead of print]70(4): 103346
      It has been known as almost all the cells consists a lipid molecule which has a considerable impact in various biological processes. Lipids have been investigated with a potential role for the formation of cellular membrane and thereby maintaining the structural integrity. Omics has placed as a combined technologies utilized for an exploaration of mechanistic actions in several kinds of molecules that make up the cells of an organism. Lipidomics has been recognized as a newly emerged branch of omics technology. This technology has the captivating factors to classify and characterize almost all the cellular lipids with the help of various analytical techniques and computational biological plateform. In lipidomics studies, structural display of several lipid biomarkers could also be analyzed and considered for actual disease diagnosis procedures. This could also replace certain traditional diagnostics method at all over the globe. Our review focuses how important this lipidomics particularly in disease diagnosis and also covers various analytical techniques and computational methods or bioinformatics tools in for the diagnosis of disease. In addtion, we also pinponted the possible role of lipids in several kinds of cellular disorders including cancer, neurodegenerative diseases, cardiovascular diseases, diabetes and obesity in human population. .
    Keywords:  Cellular disorders; Computational biology; Disease diagnosis; Lipidomics; Omics technology
  18. Cell Death Differ. 2022 Apr 26.
      Glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. We investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of anti-apoptotic BCL-xL and MCL-1 were consistently increased in GBM compared with non-malignant cells and tissue. Moreover, we found that relative to their differentiated counterparts, patient-derived GBM stem-like cells also displayed higher expression of anti-apoptotic BCL-2 family members. High anti-apoptotic BCL-xL and MCL-1 expression correlated with heightened susceptibility of GBM to BCL-2 family protein-targeting BH3-mimetics. This is indicative of increased apoptotic priming. Indeed, GBM displayed an obligate requirement for MCL-1 expression in both tumour development and maintenance. Investigating this apoptotic sensitivity, we found that sequential inhibition of BCL-xL and MCL-1 led to robust anti-tumour responses in vivo, in the absence of overt toxicity. These data demonstrate that BCL-xL and MCL-1 pro-survival function is a fundamental prerequisite for GBM survival that can be therapeutically exploited by BH3-mimetics.
  19. Analyst. 2022 Apr 26.
      Chain modifications on fatty acyls, such as methyl branching, are important to modulate the biochemical and biophysical properties of lipids. The current lipid analysis workflows which mainly rely on collisional-induced dissociation (CID) to obtain the structural information of lipids often fail in locating the chain modifications. Radical-directed dissociation (RDD) is a new type of tandem mass spectrometry (MS/MS) method capable of producing intrachain cleavages, thus allowing the detailed characterization of lipid structures. In this study, we have developed an RDD method induced by nitroxide radicals (NO˙) for the analysis of branched-chain fatty acids (BCFAs). Fatty acids (FAs) are first amidated by O-benzylhydroxylamine; MS2 CID of the lithium adduct ion of the derivatized FAs uncages the nitroxide radical, which subsequently initiates RDD along the chain. The location of methyl branching can be determined via characteristic 28 Da spacing due to cleavages on either side of the branching point, with enhanced fragmentation observed toward the carbonyl end. This nitroxide-RDD method has been integrated onto reversed-phase liquid chromatography and applied for the profiling of BCFAs from yak milk powder and pooled human plasma samples. Other than the more often encountered iso- and anteiso-BCFAs, we have identified FA n-5 17 : 0 as a minor component from human plasma, which has been rarely reported before.
  20. Prostaglandins Other Lipid Mediat. 2022 Apr 23. pii: S1098-8823(22)00028-4. [Epub ahead of print] 106638
      Estimates of heritability are the first step in identifying a trait with substantial variation due to genetic factors. Large-scale genetic analyses can identify the DNA variants that influence the levels of circulating lipid species and the statistical technique Mendelian randomisation can use these DNA variants to address potential causality of these lipids in disease. We estimated the heritability of plasma eicosanoids, octadecanoids and docosanoids to identify those lipid species with substantial heritability. We analysed plasma lipid mediators in 31 White British families (196 participants) ascertained for high blood pressure and deeply clinically and biochemically phenotyped over a 25-year period. We found that the dihydroxyeicosatrienoic acid (DHET) species, 11,12-DHET and 14,15-DHET, products of arachidonic acid metabolism by cytochrome P450 (CYP) monooxygenase and soluble epoxide hydrolase (sEH), exhibited substantial heritability (h2 = 33%-37%; Padj<0.05). Identification of these two heritable bioactive lipid species allows for future large-scale, targeted, lipidomics-genomics analyses to address causality in cardiovascular and other diseases.
    Keywords:  Heritability; dihydroxyeicosatrienoic acid; eicosanoids; genetics; lipidomics
  21. Nat Chem Biol. 2022 May;18(5): 470-481
      T cells orchestrate adaptive immunity against pathogens and other immune challenges, but their dysfunction can also mediate the pathogenesis of cancer and autoimmunity. Metabolic adaptation in response to immunological and microenvironmental signals contributes to T cell function and fate decision. Lipid metabolism has emerged as a key regulator of T cell responses, with selective lipid metabolites serving as metabolic rheostats to integrate environmental cues and interplay with intracellular signaling processes. Here, we discuss how extracellular, de novo synthesized and membrane lipids orchestrate T cell biology. We also describe the roles of lipids as regulators of intracellular signaling at the levels of transcriptional, epigenetic and post-translational regulation in T cells. Finally, we summarize therapeutic targeting of lipid metabolism and signaling, and conclude with a discussion of important future directions. Understanding the molecular and functional interplay between lipid metabolism and T cell biology will ultimately inform therapeutic intervention for human disease.
  22. Nat Cancer. 2022 Apr;3(4): 471-485
      Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.
  23. Biomed Khim. 2022 Apr;68(2): 144-152
      Research of cancer progression mechanisms and their impact on metabolism of tumor cells and tumor microenvironment cells is an important element in drug development for cancer target therapy. In this study, changes in tumor tissue and margin tissue lipid profiles, were associated with the following clinical and morphological characteristics: tumor size, cancer stage, multifocalite, tumor grade, number of lymph node metastasis, Nottingham prognostic index, total malignancy score, level of Ki67 protein. Lipid profiling was performed by reverse-phase chromato-mass spectrometry analysis of lipid tissue extract with lipid identification by characteristic fragments. In the lipid profile of tumor tissue 13 characteristic lipids were selected. Their levels significantly correlated with at least 5 clinical and morphological features. Eight of 13 belonged to phosphatidylcholines. In lipid profile of tumor microenviroment tissue 13 lipid features were selected. Their levels significantly correlated with at least 5 clinical and morphological features. Four of 13 belonged to oxidized lipids, 4 lipid features belonged to sphingomyelins, four of 13 belonged to phosphatidylethanolamines. The tumor microenvironment tissue lipid profile correlated with tumor size, cancer stage, tumor grade, number of axillary metastases, Nottingham prognostic index. The tumor tissue lipid profile correlated with tumor size, tumor grade, total malignant score, and number of axillary metastases.
    Keywords:  breast cancer; cancer progression; lipidomics; mass-spectrometry; tumor microenvironment
  24. Neoplasma. 2022 Apr 26. pii: 220119N77. [Epub ahead of print]
      Cancer is the disease of uncontrollably dividing cells in the body. As cancer cells proliferate at higher rates, they need more energy in a short time necessitating deregulation of energy-generating pathways for their benefit. Although oxidative phosphorylation generates more energy from a glucose molecule, cancer cells have a tendency to enhance aerobic glycolysis by consuming more glucose and producing lactate as a by-product even if oxygen is present. In addition to the generation of rapid energy to fulfill their increasing demands, this strategy also provides the use of glucose metabolites such as lactate as a source for the synthesis of anabolic molecules, such as nucleotides, amino acids, and lipids during the rapid phase of the proliferation. Pyruvate kinase M2 (PKM2) is an isoform of pyruvate kinase, which mediates the balancing of energy generation mechanisms during the anabolic and catabolic events. Due to its vital role in glycolysis, PKM2 has been investigated to target cancer cell metabolism for several years. However, recent studies demonstrate that PKM2 may also promote cancer progression by regulating core steps in metastasis such as migration, angiogenesis, and stemness. Of note, it is estimated that 90% of cancer-related deaths are due to metastasis. This review is intended to summarize the recent advances in the non-metabolic roles of PKM2 in cancer progression and to indicate its potential uses for the development of new treatment strategies.
  25. J Mass Spectrom Adv Clin Lab. 2022 Apr;24 50-56
      Introduction: Ion mobility-mass spectrometry (IM-MS) is an emerging technique in the -omics fields that has broad potential applicability to the clinical lab. As a rapid, gas-phase structure-based separation technique, IM-MS offers promise in isomer separations and can be easily combined with existing LC-MS methods (i.e., LC-IM-MS). Several experimental conditions, including analyte cation adducts and drift composition further provide a means to tune separations for global and/or targeted applications.Objectives: The primary objective of this study was to demonstrate the utility of IM-MS under a range of experimental conditions for detection of glucocorticoids, and specifically for the separation of several isomeric pairs.
    Methods: LC-IM-MS was used to characterize 16 glucocorticoids including three isomer pairs: cortisone/prednisolone, betamethasone/dexamethasone, and flunisolide/triamcinolone acetonide. Collision cross section (CCS) values were measured for all common adducts (e.g., protonated and sodiated) using both step-field and single-field methods. Alternative alkali, alkaline earth, and transition metals were introduced, such that their adducts could also be measured. Finally, four different drift gases (helium, nitrogen, argon, and carbon dioxide) were compared for their relative separation capability.
    Results: LC-IM-MS offered a robust, multidimensional separation technique that allowed for the 16 glucocorticoids to be analyzed and separated in three-dimensions (retention time, CCS, and m/z). Despite the relatively modest resolution of isomer pairs under standard conditions (i.e., nitrogen drift gas, sodiated ions, etc.), improvements were observed for alkaline earth and transition metals (notable barium adducts) and in carbon dioxide drift gas.
    Conclusion: In summary, LC-IM-MS offers potential as a clinical method due to its ease of coupling with traditional LC-MS methods and its promise for tuning separations to better resolve targeted and/or global isomers in complex biological samples.
    Keywords:  CCS, collision cross section; CIMS, cyclic ion mobility spectrometry; DMS, differential mobility spectrometry; DTIMS, drift tube ion mobility spectrometry; FAIMS, field asymmetric ion mobility spectrometry; Glucocorticoids; IM-MS, ion mobility-mass spectrometry; IMS, ion mobility spectrometry; Ion mobility spectrometry; Ion mobility-mass spectrometry; SLIM, structures for lossless ion manipulations; TIMS, trapped ion mobility spectrometry; TWIMS, traveling wave ion mobility spectrometry