bims-mascan Biomed News
on Mass spectrometry in cancer research
Issue of 2023–03–05
sixteen papers selected by
Giovanny Rodriguez Blanco, University of Edinburgh
  1. What is cancer metabolism?
  2. FAMetA: a mass isotopologue-based tool for the comprehensive analysis of fatty acid metabolism.
  3. Glutamine metabolism in breast cancer and possible therapeutic targets.
  4. Optimizing linear ion trap data independent acquisition towards single cell proteomics.
  5. Editorial: Advances and challenges in untargeted metabolomics.
  6. Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism.
  7. Interpreting metabolic complexity via isotope-assisted metabolic flux analysis.
  8. Enhanced Multiplexing Technology for Proteomics.
  9. Initial recommendations for performing, benchmarking and reporting single-cell proteomics experiments.
  10. Structural Analysis of Intracellular Lipid Radicals by LC/MS/MS Using a BODIPY-Based Profluorescent Nitroxide Probe.
  11. Model-driven data curation pipeline for LC-MS-based untargeted metabolomics.
  12. Comprehensive Metabolic Tracing Reveals the Origin and Catabolism of Cysteine in Mammalian Tissues and Tumors.
  13. Functional states of myeloid cells in cancer.
  14. Fatty acids prime the lung as a site for tumour spread.
  15. Cardinal v3 - a versatile open source software for mass spectrometry imaging analysis.
  16. Targeting acetyl-CoA carboxylase 1 for cancer therapy.
  1. Cell. 2023 Feb 22. pii: S0092-8674(23)00097-1. [Epub ahead of print]
    What is cancer metabolism?
    Lydia W S Finley.
      The uptake and metabolism of nutrients support fundamental cellular process from bioenergetics to biomass production and cell fate regulation. While many studies of cell metabolism focus on cancer cells, the principles of metabolism elucidated in cancer cells apply to a wide range of mammalian cells. The goal of this review is to discuss how the field of cancer metabolism provides a framework for revealing principles of cell metabolism and for dissecting the metabolic networks that allow cells to meet their specific demands. Understanding context-specific metabolic preferences and liabilities will unlock new approaches to target cancer cells to improve patient care.
    DOI:  https://doi.org/10.1016/j.cell.2023.01.038
  2. Brief Bioinform. 2023 Mar 01. pii: bbad064. [Epub ahead of print]
    FAMetA: a mass isotopologue-based tool for the comprehensive analysis of fatty acid metabolism.
    María I Alcoriza-Balaguer, Juan C García-Cañaveras, Marta Benet, Oscar Juan-Vidal, Agustín Lahoz.
      The use of stable isotope tracers and mass spectrometry (MS) is the gold standard method for the analysis of fatty acid (FA) metabolism. Yet, current state-of-the-art tools provide limited and difficult-to-interpret information about FA biosynthetic routes. Here we present FAMetA, an R package and a web-based application (www.fameta.es) that uses 13C mass isotopologue profiles to estimate FA import, de novo lipogenesis, elongation and desaturation in a user-friendly platform. The FAMetA workflow covers the required functionalities needed for MS data analyses. To illustrate its utility, different in vitro and in vivo experimental settings are used in which FA metabolism is modified. Thanks to the comprehensive characterization of FA biosynthesis and the easy-to-interpret graphical representations compared to previous tools, FAMetA discloses unnoticed insights into how cells reprogram their FA metabolism and, when combined with FASN, SCD1 and FADS2 inhibitors, it enables the identification of new FAs by the metabolic reconstruction of their synthesis route.
    Keywords:  fatty acids; inhibitors; lipid metabolism; mass spectrometry; stable isotopes
    DOI:  https://doi.org/10.1093/bib/bbad064
  3. Biochem Pharmacol. 2023 Feb 25. pii: S0006-2952(23)00055-2. [Epub ahead of print] 115464
    Glutamine metabolism in breast cancer and possible therapeutic targets.
    Shiqi Li, Hui Zeng, Junli Fan, Fubing Wang, Chen Xu, Yirong Li, Jiancheng Tu, Kenneth P Nephew, Xinghua Long.
      Cancer is characterized by metabolic reprogramming, which is a hot topic in tumor treatment research. Cancer cells alter metabolic pathways to promote their growth, and the common purpose of these altered metabolic pathways is to adapt the metabolic state to the uncontrolled proliferation of cancer cells. Most cancer cells in a state of nonhypoxia will increase the uptake of glucose and produce lactate, called the Warburg effect. Increased glucose consumption is used as a carbon source to support cell proliferation, including nucleotide, lipid and protein synthesis. In the Warburg effect, pyruvate dehydrogenase activity decreases, thereby disrupting the TCA cycle. In addition to glucose, glutamine is also an important nutrient for the growth and proliferation of cancer cells, an important carbon bank and nitrogen bank for the growth and proliferation of cancer cells, providing ribose, nonessential amino acids, citrate, and glycerin necessary for cancer cell growth and proliferation and compensating for the reduction in oxidative phosphorylation pathways in cancer cells caused by the Warburg effect. In human plasma, glutamine is the most abundant amino acid. Normal cells produce glutamine via glutamine synthase (GLS), but the glutamine synthesized by tumor cells is insufficient to meet their high growth needs, resulting in a "glutamine-dependent phenomenon." Most cancers have an increased glutamine demand, including breast cancer. Metabolic reprogramming not only enables tumor cells to maintain the reduction-oxidation (redox) balance and commit resources to biosynthesis but also establishes heterogeneous metabolic phenotypes of tumor cells that are distinct from those of nontumor cells. Thus, targeting the metabolic differences between tumor and nontumor cells may be a promising and novel anticancer strategy. Glutamine metabolic compartments have emerged as promising candidates, especially in TNBC and drug-resistant breast cancer. In this review, the latest discoveries of breast cancer and glutamine metabolism are discussed, novel treatment methods based on amino acid transporters and glutaminase are discussed, and the relationship between glutamine metabolism and breast cancer metastasis, drug resistance, tumor immunity and ferroptosis are explained, which provides new ideas for the clinical treatment of breast cancer.
    Keywords:  Amino acid transporters; Breast cancer; Glutaminase; Glutamine metabolism; Immune microenvironment; ferroptosis
    DOI:  https://doi.org/10.1016/j.bcp.2023.115464
  4. bioRxiv. 2023 Feb 21. pii: 2023.02.21.529444. [Epub ahead of print]
    Optimizing linear ion trap data independent acquisition towards single cell proteomics.
    Teeradon Phlairaharn, Zilu Ye, Elena Krismer, Anna-Kathrine Pedersen, Maik Pietzner, Jesper V Olsen, Erwin M Schoof, Brian C Searle.
      A linear ion trap (LIT) is an affordable, robust mass spectrometer that proves fast scanning speed and high sensitivity, where its primary disadvantage is inferior mass accuracy compared to more commonly used time-of-flight (TOF) or orbitrap (OT) mass analyzers. Previous efforts to utilize the LIT for low-input proteomics analysis still rely on either built-in OTs for collecting precursor data or OT-based library generation. Here, we demonstrate the potential versatility of the LIT for low-input proteomics as a stand-alone mass analyzer for all mass spectrometry measurements, including library generation. To test this approach, we first optimized LIT data acquisition methods and performed library-free searches with and without entrapment peptides to evaluate both the detection and quantification accuracy. We then generated matrix-matched calibration curves to estimate the lower limit of quantification using only 10 ng of starting material. While LIT-MS1 measurements provided poor quantitative accuracy, LIT-MS2 measurements were quantitatively accurate down to 0.5 ng on column. Finally, we optimized a suitable strategy for spectral library generation from low-input material, which we used to analyze single-cell samples by LIT-DIA using LIT-based libraries generated from as few as 40 cells.
    DOI:  https://doi.org/10.1101/2023.02.21.529444
  5. Front Mol Biosci. 2023 ;10 1097443
    Editorial: Advances and challenges in untargeted metabolomics.
    Renata Wawrzyniak, Franciso Javier Ruperez, Joanna Barbara Godzień.
      
    Keywords:  analytical methods; applications; data processing and analysis; metabolite identification; sample preparation; untargeted (global) metabolomics
    DOI:  https://doi.org/10.3389/fmolb.2023.1097443
  6. Nat Commun. 2023 Mar 02. 14(1): 1187
    Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism.
    Pavan S Upadhyayula, Dominique M Higgins, Angeliki Mela, Matei Banu, Athanassios Dovas, Fereshteh Zandkarimi, Purvi Patel, Aayushi Mahajan, Nelson Humala, Trang T T Nguyen, Kunal R Chaudhary, Lillian Liao, Michael Argenziano, Tejaswi Sudhakar, Colin P Sperring, Benjamin L Shapiro, Eman R Ahmed, Connor Kinslow, Ling F Ye, Markus D Siegelin, Simon Cheng, Rajesh Soni, Jeffrey N Bruce, Brent R Stockwell, Peter Canoll.
      Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.
    DOI:  https://doi.org/10.1038/s41467-023-36630-w
  7. Trends Biochem Sci. 2023 Feb 28. pii: S0968-0004(23)00034-8. [Epub ahead of print]
    Interpreting metabolic complexity via isotope-assisted metabolic flux analysis.
    Bilal Moiz, Ganesh Sriram, Alisa Morss Clyne.
      Isotope-assisted metabolic flux analysis (iMFA) is a powerful method to mathematically determine the metabolic fluxome from experimental isotope labeling data and a metabolic network model. While iMFA was originally developed for industrial biotechnological applications, it is increasingly used to analyze eukaryotic cell metabolism in physiological and pathological states. In this review, we explain how iMFA estimates the intracellular fluxome, including data and network model (inputs), the optimization-based data fitting (process), and the flux map (output). We then describe how iMFA enables analysis of metabolic complexities and discovery of metabolic pathways. Our goal is to expand the use of iMFA in metabolism research, which is essential to maximizing the impact of metabolic experiments and continuing to advance iMFA and biocomputational techniques.
    Keywords:  fluxomics; mass spectrometry; metabolic modeling isotope labeling
    DOI:  https://doi.org/10.1016/j.tibs.2023.02.001
  8. Annu Rev Anal Chem (Palo Alto Calif). 2022 Feb 28.
    Enhanced Multiplexing Technology for Proteomics.
    Bailey L Bowser, Renã A S Robinson.
      The identification of thousands of proteins and their relative levels of expression has furthered understanding of biological processes and disease and stimulated new systems biology hypotheses. Quantitative proteomics workflows that rely on analytical assays such as mass spectrometry have facilitated high-throughput measurements of proteins partially due to multiplexing. Multiplexing allows proteome differences across multiple samples to be measured simultaneously, resulting in more accurate quantitation, increased statistical robustness, reduced analysis times, and lower experimental costs. The number of samples that can be multiplexed has evolved from as few as two to more than 50, with studies involving more than 10 samples being denoted as enhanced multiplexing or hyperplexing. In this review, we give an update on emerging multiplexing proteomics techniques and highlight advantages and limitations for enhanced multiplexing strategies. Expected final online publication date for the Annual Review of Analytical Chemistry, Volume 16 is June 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-anchem-091622-092353
  9. Nat Methods. 2023 Mar 02.
    Initial recommendations for performing, benchmarking and reporting single-cell proteomics experiments.
    Laurent Gatto, Ruedi Aebersold, Juergen Cox, Vadim Demichev, Jason Derks, Edward Emmott, Alexander M Franks, Alexander R Ivanov, Ryan T Kelly, Luke Khoury, Andrew Leduc, Michael J MacCoss, Peter Nemes, David H Perlman, Aleksandra A Petelski, Christopher M Rose, Erwin M Schoof, Jennifer Van Eyk, Christophe Vanderaa, John R Yates, Nikolai Slavov.
      Analyzing proteins from single cells by tandem mass spectrometry (MS) has recently become technically feasible. While such analysis has the potential to accurately quantify thousands of proteins across thousands of single cells, the accuracy and reproducibility of the results may be undermined by numerous factors affecting experimental design, sample preparation, data acquisition and data analysis. We expect that broadly accepted community guidelines and standardized metrics will enhance rigor, data quality and alignment between laboratories. Here we propose best practices, quality controls and data-reporting recommendations to assist in the broad adoption of reliable quantitative workflows for single-cell proteomics. Resources and discussion forums are available at https://single-cell.net/guidelines .
    DOI:  https://doi.org/10.1038/s41592-023-01785-3
  10. Anal Chem. 2023 Feb 27.
    Structural Analysis of Intracellular Lipid Radicals by LC/MS/MS Using a BODIPY-Based Profluorescent Nitroxide Probe.
    Takumi Udo, Yuta Matsuoka, Masatomo Takahashi, Yoshihiro Izumi, Kota Saito, Kaho Tazoe, Moe Tanaka, Hideto Naka, Takeshi Bamba, Ken-Ichi Yamada.
      Free radical-mediated lipid peroxidation (LPO) induces the formation of numerous lipid radicals, which contribute to the development of several oxidative diseases. To understand the mechanism of LPO in biological systems and the significance of these radicals, identifying the structures of individual lipid radicals is imperative. In this study, we developed an analytical method based on liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and a profluorescent nitroxide probe, N-(1-oxyl-2,2,6-trimethyl-6-pentylpiperidin-4-yl)-3-(5,5-difluoro-1,3-dimethyl-3H,5H-5l4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-7-yl)propanamide (BDP-Pen), for the detailed structural analysis of lipid radicals. The MS/MS spectra of BDP-Pen-lipid radical adducts showed product ions and thus allow the prediction of the lipid radical structures and individual detection of isomeric adducts. Using the developed technology, we separately detected the isomers of arachidonic acid (AA)-derived radicals generated in AA-treated HT1080 cells. This analytical system is a powerful tool for elucidating the mechanism of LPO in biological systems.
    DOI:  https://doi.org/10.1021/acs.analchem.2c04950
  11. Metabolomics. 2023 Mar 01. 19(3): 15
    Model-driven data curation pipeline for LC-MS-based untargeted metabolomics.
    Gabriel Riquelme, Emmanuel Ezequiel Bortolotto, Matías Dombald, María Eugenia.
       INTRODUCTION: There is still no community consensus regarding strategies for data quality review in liquid chromatography mass spectrometry (LC-MS)-based untargeted metabolomics. Assessing the analytical robustness of data, which is relevant for inter-laboratory comparisons and reproducibility, remains a challenge despite the wide variety of tools available for data processing.
    OBJECTIVES: The aim of this study was to provide a model to describe the sources of variation in LC-MS-based untargeted metabolomics measurements, to use it to build a comprehensive curation pipeline, and to provide quality assessment tools for data quality review.
    METHODS: Human serum samples (n=392) were analyzed by ultraperformance liquid chromatography coupled to high-resolution mass spectrometry (UPLC-HRMS) using an untargeted metabolomics approach. The pipeline and tools used to process this dataset were implemented as part of the open source, publicly available TidyMS Python-based package.
    RESULTS: The model was applied to understand data curation practices used by the metabolomics community. Sources of variation, which are often overlooked in untargeted metabolomic studies, were identified in the analysis. New tools were used to characterize certain types of variations.
    CONCLUSION: The developed pipeline allowed confirming data robustness by comparing the experimental results with expected values predicted by the model. New quality control practices were introduced to assess the analytical quality of data.
    Keywords:  Data curation; Liquid chromatography; Mass spectrometry; Quality control practices
    DOI:  https://doi.org/10.1007/s11306-023-01976-1
  12. Cancer Res. 2023 Mar 02. pii: CAN-22-3000. [Epub ahead of print]
    Comprehensive Metabolic Tracing Reveals the Origin and Catabolism of Cysteine in Mammalian Tissues and Tumors.
    Sang Jun Yoon, Joseph A Combs, Aimee Falzone, Nicolas Prieto-Farigua, Samantha Caldwell, Hayley D Ackerman, Elsa R Flores, Gina M DeNicola.
      Cysteine plays critical roles in cellular biosynthesis, enzyme catalysis, and redox metabolism. The intracellular cysteine pool can be sustained by cystine uptake or de novo synthesis from serine and homocysteine. Demand for cysteine is increased during tumorigenesis for generating glutathione to deal with oxidative stress. While cultured cells have been shown to be highly dependent on exogenous cystine for proliferation and survival, how diverse tissues obtain and use cysteine in vivo has not been characterized. We comprehensively interrogated cysteine metabolism in normal murine tissues and cancers that arise from them using stable isotope 13C1-serine and 13C6-cystine tracing. De novo cysteine synthesis was highest in normal liver and pancreas and absent in lung tissue, while cysteine synthesis was either inactive or downregulated during tumorigenesis. By contrast, cystine uptake and metabolism to downstream metabolites was a universal feature of normal tissues and tumors. However, differences in glutathione labeling from cysteine were evident across tumor types. Thus, cystine is a major contributor to the cysteine pool in tumors, and glutathione metabolism is differentially active across tumor types.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-3000
  13. Cancer Cell. 2023 Mar 01. pii: S1535-6108(23)00037-5. [Epub ahead of print]
    Functional states of myeloid cells in cancer.
    Lilian van Vlerken-Ysla, Yulia Y Tyurina, Valerian E Kagan, Dmitry I Gabrilovich.
      Myeloid cells, comprised of macrophages, dendritic cells, monocytes, and granulocytes, represent a major component of the tumor microenvironment (TME) and are critically involved in regulation of tumor progression and metastasis. In recent years, single-cell omics technologies have identified multiple phenotypically distinct subpopulations. In this review, we discuss recent data and concepts suggesting that the biology of myeloid cells is largely defined by a very limited number of functional states that transcend the narrowly defined cell populations. These functional states are primarily centered around classical and pathological states of activation, with the latter state commonly defined as myeloid-derived suppressor cells. We discuss the concept that lipid peroxidation of myeloid cells represents a major mechanism that governs their pathological state of activation in the TME. Lipid peroxidation is associated with ferroptosis mediating suppressive activity of these cells and thus could be considered an attractive target for therapeutic intervention.
    Keywords:  ferroptosis; lipid peroxidation; macrophages; monocytes; myeloid-derived suppressor cells; neutrophils
    DOI:  https://doi.org/10.1016/j.ccell.2023.02.009
  14. Nature. 2023 Feb 28.
    Fatty acids prime the lung as a site for tumour spread.
    Laura V Pinheiro, Kathryn E Wellen.
      
    Keywords:  Cancer; Medical research; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-00538-8
  15. bioRxiv. 2023 Feb 21. pii: 2023.02.20.529280. [Epub ahead of print]
    Cardinal v3 - a versatile open source software for mass spectrometry imaging analysis.
    Kylie Ariel Bemis, Melanie Christine Föll, Dan Guo, Sai Srikanth Lakkimsetty, Olga Vitek.
      Cardinal v3 is an open source software for reproducible analysis of mass spectrometry imaging experiments. A major update from its previous versions, Cardinal v3 supports most mass spectrometry imaging workflows. Its analytical capabilities include advanced data processing such as mass re-calibration, advanced statistical analyses such as single-ion segmentation and rough annotation-based classification, and memory-efficient analyses of large-scale multi-tissue experiments.
    DOI:  https://doi.org/10.1101/2023.02.20.529280
  16. Front Pharmacol. 2023 ;14 1129010
    Targeting acetyl-CoA carboxylase 1 for cancer therapy.
    Yong Yu, Qingzhu Nie, Ziyi Wang, Yu Di, Xiaolong Chen, Kaiming Ren.
      Metabolic adaptation is an emerging hallmark of tumors. De novo fatty acid synthesis is an important metabolic process to produce metabolic intermediates for energy storage, biosynthesis of membrane lipids and generation of signaling molecules. Acetyl-CoA carboxylase 1 (ACC1) is a critical enzyme in the fatty acid synthesis, which carboxylates acetyl-CoA carboxylic acid to form malonyl-CoA. The role of acetyl-CoA carboxylase 1 in fatty acid synthesis makes it a promising therapeutic target for various metabolic diseases such as non-alcoholic fatty liver disease, obesity and diabetes. Tumors have a high energy flow and a strong dependence on fatty acid synthesis. Thus, acetyl-CoA carboxylase inhibition has become a potential choice for anti-tumor therapy. In this review, we first introduced the structure and expression pattern of Acetyl-CoA carboxylase 1. We also discussed the molecular mechanisms of acetyl-CoA carboxylase 1 in the initiation and progression of various cancer types. Furthermore, acetyl-CoA carboxylase1 inhibitors has also been discussed. Collectively, we summarized the interplay between acetyl-CoA carboxylase 1 and tumorigenesis, indicating acetyl-CoA carboxylase 1 as a promising therapeutic target for tumor management.
    Keywords:  acetyl-CoA carboxylase 1; cancer; fatty acid; fatty acid synthesis; metabolism
    DOI:  https://doi.org/10.3389/fphar.2023.1129010
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