bims-mascan Biomed News
on Mass spectrometry in cancer research
Issue of 2023‒10‒29
twenty-one papers selected by
Giovanny Rodriguez Blanco, University of Edinburgh



  1. Bioinformatics. 2023 Oct 27. pii: btad661. [Epub ahead of print]
      The analysis of stable isotope labeling experiments requires accurate, efficient, and reproducible quantification of mass isotopomer distributions (MIDs), which is not a core feature of general-purpose metabolomics software tools that are optimized to quantify metabolite abundance. Here we present PIRAMID, a MATLAB-based tool that addresses this need by offering a user-friendly, graphical user interface (GUI)-driven program to automate the extraction of isotopic information from mass spectrometry (MS) data sets. This tool can simultaneously extract ion chromatograms for various metabolites from multiple data files in common vendor-agnostic file formats, locate chromatographic peaks based on a targeted list of characteristic ions and retention times, and integrate MIDs for each target ion. These MIDs can be corrected for natural isotopic background based on the user-defined molecular formula of each ion. PIRAMID offers support for datasets acquired from low- or high-resolution (HR) MS, and single (MS) or tandem (MS/MS) instruments. It also enables the analysis of single or dual labeling experiments using a variety of isotopes (i.e., 2H, 13C, 15N, 18O, 34S).AVAILABILITY: MATLAB p-code files are freely available for non-commercial use and can be downloaded from https://mfa.vueinnovations.com/. Commercial licenses are also available.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btad661
  2. Biomedicines. 2023 Oct 19. pii: 2842. [Epub ahead of print]11(10):
      Using an untargeted stable isotope-assisted metabolomics approach, we identify erythronate as a metabolite that accumulates in several human cancer cell lines. Erythronate has been reported to be a detoxification product derived from off-target glycolytic metabolism. We use chemical inhibitors and genetic silencing to define the pentose phosphate pathway intermediate erythrose 4-phosphate (E4P) as the starting substrate for erythronate production. However, following enzyme assay-coupled protein fractionation and subsequent proteomics analysis, we identify aldehyde dehydrogenase 1A1 (ALDH1A1) as the predominant contributor to erythrose oxidation to erythronate in cell extracts. Through modulating ALDH1A1 expression in cancer cell lines, we provide additional support. We hence describe a possible alternative route to erythronate production involving the dephosphorylation of E4P to form erythrose, followed by its oxidation by ALDH1A1. Finally, we measure increased erythronate concentrations in tumors relative to adjacent normal tissues from lung cancer patients. These findings suggest the accumulation of erythronate to be an example of metabolic reprogramming in cancer cells, raising the possibility that elevated levels of erythronate may serve as a biomarker of certain types of cancer.
    Keywords:  aldehyde dehydrogenase 1A1 (ALDH1A1); cancer metabolism; erythronate; pentose phosphate pathway; untargeted metabolomics
    DOI:  https://doi.org/10.3390/biomedicines11102842
  3. Metabolites. 2023 Oct 02. pii: 1047. [Epub ahead of print]13(10):
      Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is the third leading cause of mortality globally. Patients with HCC have a poor prognosis due to the fact that the emergence of symptoms typically occurs at a late stage of the disease. In addition, conventional biomarkers perform suboptimally when identifying HCC in its early stages, heightening the need for the identification of new and more effective biomarkers. Using metabolomics and lipidomics approaches, this study aims to identify serum biomarkers for identification of HCC in patients with liver cirrhosis (LC). Serum samples from 20 HCC cases and 20 patients with LC were analyzed using ultra-high-performance liquid chromatography-Q Exactive mass spectrometry (UHPLC-Q-Exactive-MS). Metabolites and lipids that are significantly altered between HCC cases and patients with LC were identified. These include organic acids, amino acids, TCA cycle intermediates, fatty acids, bile acids, glycerophospholipids, sphingolipids, and glycerolipids. The most significant variability was observed in the concentrations of bile acids, fatty acids, and glycerophospholipids. In the context of HCC cases, there was a notable increase in the levels of phosphatidylethanolamine and triglycerides, but the levels of fatty acids and phosphatidylcholine exhibited a substantial decrease. In addition, it was observed that all of the identified metabolites exhibited a superior area under the receiver operating characteristic (ROC) curve in comparison to alpha-fetoprotein (AFP). The pathway analysis of these metabolites revealed fatty acid, lipid, and energy metabolism as the most impacted pathways. Putative biomarkers identified in this study will be validated in future studies via targeted quantification.
    Keywords:  LC-MS/MS; biomarkers; lipidomic profiling; liver cancer; metabolomic profiling
    DOI:  https://doi.org/10.3390/metabo13101047
  4. Proteomes. 2023 Oct 16. pii: 32. [Epub ahead of print]11(4):
      Rheumatoid arthritis (RA) is a systemic autoimmune and inflammatory disease. Plasma biomarkers are critical for understanding disease mechanisms, treatment effects, and diagnosis. Mass spectrometry-based proteomics is a powerful tool for unbiased biomarker discovery. However, plasma proteomics is significantly hampered by signal interference from high-abundance proteins, low overall protein coverage, and high levels of missing data from data-dependent acquisition (DDA). To achieve quantitative proteomics analysis for plasma samples with a balance of throughput, performance, and cost, we developed a workflow incorporating plate-based high abundance protein depletion and sample preparation, comprehensive peptide spectral library building, and data-independent acquisition (DIA) SWATH mass spectrometry-based methodology. In this study, we analyzed plasma samples from both RA patients and healthy donors. The results showed that the new workflow performance exceeded that of the current state-of-the-art depletion-based plasma proteomic platforms in terms of both data quality and proteome coverage. Proteins from biological processes related to the activation of systemic inflammation, suppression of platelet function, and loss of muscle mass were enriched and differentially expressed in RA. Some plasma proteins, particularly acute-phase reactant proteins, showed great power to distinguish between RA patients and healthy donors. Moreover, protein isoforms in the plasma were also analyzed, providing even deeper proteome coverage. This workflow can serve as a basis for further application in discovering plasma biomarkers of other diseases.
    Keywords:  DIA; SWATH; biomarker; plasma; protein isoform; proteomics; rheumatoid arthritis
    DOI:  https://doi.org/10.3390/proteomes11040032
  5. Rapid Commun Mass Spectrom. 2023 Oct 26. e9641
      Extraction protocols and liquid chromatography coupled with mass spectrometry (LC-MS) and tandem mass spectrometry (LC-MS/MS) methods for the measurement of four lipid categories, namely glycerophospholipids, glycerolipids, sphingolipids and sterol lipids in human plasma, are described here. Step-by-step instructions are provided for the liquid-liquid extraction methods, including solution preparation and the non-endogenous lipid internal standards used. All instrumental conditions, chromatography columns and solutions required for the LC-MS and LC-MS/MS methods are also provided in detail.
    DOI:  https://doi.org/10.1002/rcm.9641
  6. Biomed Pharmacother. 2023 Oct 19. pii: S0753-3322(23)01539-1. [Epub ahead of print]168 115741
      Acetyl-coenzyme A (acetyl-CoA), an essential metabolite, not only takes part in numerous intracellular metabolic processes, powers the tricarboxylic acid cycle, serves as a key hub for the biosynthesis of fatty acids and isoprenoids, but also serves as a signaling substrate for acetylation reactions in post-translational modification of proteins, which is crucial for the epigenetic inheritance of cells. Acetyl-CoA links lipid metabolism with histone acetylation to create a more intricate regulatory system that affects the growth, aggressiveness, and drug resistance of malignancies such as glioblastoma, breast cancer, and hepatocellular carcinoma. These fascinating advances in the knowledge of acetyl-CoA metabolism during carcinogenesis and normal physiology have raised interest regarding its modulation in malignancies. In this review, we provide an overview of the regulation and cancer relevance of main metabolic pathways in which acetyl-CoA participates. We also summarize the role of acetyl-CoA in the metabolic reprogramming and stress regulation of cancer cells, as well as medical application of inhibitors targeting its dysregulation in therapeutic intervention of cancers.
    Keywords:  Acetyl-coenzyme A metabolism; Cancer progression; Cancer therapy; Metabolic reprogramming; Protein acetylation
    DOI:  https://doi.org/10.1016/j.biopha.2023.115741
  7. J Am Soc Mass Spectrom. 2023 Oct 24.
      Liquid chromatography-mass spectrometry (LC-MS) metabolomics studies produce high-dimensional data that must be processed by a complex network of informatics tools to generate analysis-ready data sets. As the first computational step in metabolomics, data processing is increasingly becoming a challenge for researchers to develop customized computational workflows that are applicable for LC-MS metabolomics analysis. Ontology-based automated workflow composition (AWC) systems provide a feasible approach for developing computational workflows that consume high-dimensional molecular data. We used the Automated Pipeline Explorer (APE) to create an AWC for LC-MS metabolomics data processing across three use cases. Our results show that APE predicted 145 data processing workflows across all the three use cases. We identified six traditional workflows and six novel workflows. Through manual review, we found that one-third of novel workflows were executable whereby the data processing function could be completed without obtaining an error. When selecting the top six workflows from each use case, the computational viable rate of our predicted workflows reached 45%. Collectively, our study demonstrates the feasibility of developing an AWC system for LC-MS metabolomics data processing.
    DOI:  https://doi.org/10.1021/jasms.3c00248
  8. bioRxiv. 2023 Oct 11. pii: 2023.10.09.561530. [Epub ahead of print]
      The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo , others are auxotrophic for serine and therefore reliant on the uptake of exogenous serine. Importantly, however, the transporter(s) that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (coded for by the gene SLC1A5 ) as the primary serine transporter in cancer cells. ASCT2 is well-known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that ERα promotes serine uptake by directly activating SLC1A5 transcription. Together, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target in serine metabolism.
    DOI:  https://doi.org/10.1101/2023.10.09.561530
  9. bioRxiv. 2023 Oct 09. pii: 2023.10.06.561131. [Epub ahead of print]
      Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NAPDH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer model, we show that ablation of G6PD significantly suppresses Kras G12D/+ ;Lkb1 -/- (KL) but not Kras G12D/+ ;p53 -/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics revealed that G6PD ablation significantly impaired NADPH generation, redox balance and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation caused p53 activation that suppressed tumor growth. As tumor progressed, G6PD-deficient KL tumors increased an alternative NADPH source, serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.
    DOI:  https://doi.org/10.1101/2023.10.06.561131
  10. Medicina (Kaunas). 2023 Sep 27. pii: 1722. [Epub ahead of print]59(10):
      Mass spectrometry-based proteomics is a key player in research efforts to characterize aberrant epigenetic alterations, including histone post-translational modifications and DNA methylation. Data generated by this approach complements and enrich datasets generated by genomic, epigenetic and transcriptomics approaches. These combined datasets can provide much-needed information on various mechanisms responsible for drug resistance, the discovery and validation of potential biomarkers for different diseases, the identification of signaling pathways, and genes and enzymes to be targeted by future therapies. The increasing use of high-resolution, high-accuracy mass spectrometers combined with more refined protein labeling and enrichment procedures enhanced the role of this approach in the investigation of these epigenetic modifications. In this review, we discuss recent MS-based studies, which are contributing to current research efforts to understand certain mechanisms behind drug resistance to therapy. We also discuss how these MS-based analyses are contributing to biomarkers discovery and validation.
    Keywords:  drug resistance; mass spectrometry; post-translational modifications
    DOI:  https://doi.org/10.3390/medicina59101722
  11. J Am Soc Mass Spectrom. 2023 Oct 23.
      Extracellular vesicles (EVs) have emerged as a promising source of disease biomarkers for noninvasive early stage diagnoses, but a bottleneck in EV sample processing restricts their immense potential in clinical applications. Existing methods are limited by a low EV yield and integrity, slow processing speeds, low sample capacity, and poor recovery efficiency. We aimed to address these issues with a high-throughput automated workflow for EV isolation, EV lysis, protein extraction, and protein denaturation. The automation can process clinical urine samples in parallel, resulting in protein-covered beads ready for various analytical methods, including immunoassays, protein quantitation assays, and mass spectrometry. Compared to the standard manual lysis method for contamination levels, efficiency, and consistency of EV isolation, the automated protocol shows reproducible and robust proteomic quantitation with less than a 10% median coefficient of variation. When we applied the method to clinical samples, we identified a total 3,793 unique proteins and 40,380 unique peptides, with 992 significantly upregulated proteins in kidney cancer patients versus healthy controls. These upregulated proteins were found to be involved in several important kidney cancer metabolic pathways also identified with a manual control. This hands-free workflow represents a practical EV extraction and profiling approach that can benefit both clinical and research applications, streamlining biomarker discovery, tumor monitoring, and early cancer diagnoses.
    Keywords:  EVTrap; automation; extracellular vesicles; kidney cancer; proteomics; urine
    DOI:  https://doi.org/10.1021/jasms.3c00329
  12. Metabolites. 2023 Oct 05. pii: 1052. [Epub ahead of print]13(10):
      Cellular metabolomics provides insights into the metabolic processes occurring within cells and can help researchers understand how these processes are regulated and how they relate to cellular function, health, and disease. In this technical note, we investigated the effects of solvent evaporation equipment and storage condition on high-coverage cellular metabolomics. We previously introduced a robust CIL LC-MS-based cellular metabolomics workflow that encompasses various steps, including cell harvest, metabolic quenching, cell lysis, metabolite extraction, differential chemical isotope labeling, and LC-MS analysis. This workflow has consistently served as the cornerstone of our collaborative research and service projects. As a core facility catering to users with diverse research needs and financial resources, we have encountered scenarios requiring short-term sample storage. For example, the need often arises to transport samples at room temperature from user sites to our core facility. Herein, we present a study in which we compared different solvent evaporation methods (specifically, the nitrogen blowdown evaporator, SpeedVac concentrator, and lyophilizer) and diverse storage conditions (including dried samples stored in a freezer, samples stored in a freezer with methanol, dried samples stored at room temperature, and samples stored at room temperature with methanol). Our findings indicate that the choice of solvent evaporation equipment did not significantly impact the cellular metabolome. However, we observed a noteworthy change in the metabolome after 7 days of storage when cells were stored with methanol, regardless of whether they were kept at -80 °C or room temperature, in contrast to cells that were dried and frozen. Importantly, we detected no significant alterations in cells that were dried and stored at room temperature. In conclusion, to ensure the production of high-quality CIL LC-MS metabolomics results, we strongly recommend that, in situations where low-temperature storage is not feasible, cell samples should be thoroughly dried before storage or shipment at room temperature.
    Keywords:  LC-MS; chemical isotope labeling; metabolomics; sample shipment; sample storage
    DOI:  https://doi.org/10.3390/metabo13101052
  13. PLoS Biol. 2023 Oct;21(10): e3002354
      The N-terminal tails of eukaryotic histones are frequently posttranslationally modified. The role of these modifications in transcriptional regulation is well-documented. However, the extent to which the enzymatic processes of histone posttranslational modification might affect metabolic regulation is less clear. Here, we investigated how histone methylation might affect metabolism using metabolomics, proteomics, and RNA-seq data from cancer cell lines, primary tumour samples and healthy tissue samples. In cancer, the expression of histone methyltransferases (HMTs) was inversely correlated to the activity of NNMT, an enzyme previously characterised as a methyl sink that disposes of excess methyl groups carried by the universal methyl donor S-adenosyl methionine (SAM or AdoMet). In healthy tissues, histone methylation was inversely correlated to the levels of an alternative methyl sink, PEMT. These associations affected the levels of multiple histone marks on chromatin genome-wide but had no detectable impact on transcriptional regulation. We show that HMTs with a variety of different associations to transcription are co-regulated by the Retinoblastoma (Rb) tumour suppressor in human cells. Rb-mutant cancers show increased total HMT activity and down-regulation of NNMT. Together, our results suggest that the total activity of HMTs affects SAM metabolism, independent of transcriptional regulation.
    DOI:  https://doi.org/10.1371/journal.pbio.3002354
  14. Front Immunol. 2023 ;14 1254948
      Proteomics is the characterization of the protein composition, the proteome, of a biological sample. It involves the large-scale identification and quantification of proteins, peptides, and post-translational modifications. This review focuses on recent developments in mass spectrometry-based proteomics and provides an overview of available methods for sample preparation to study the innate immune system. Recent advancements in the proteomics workflows, including sample preparation, have significantly improved the sensitivity and proteome coverage of biological samples including the technically difficult blood plasma. Proteomics is often applied in immunology and has been used to characterize the levels of innate immune system components after perturbations such as birth or during chronic inflammatory diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In cancers, the tumor microenvironment may generate chronic inflammation and release cytokines to the circulation. In these situations, the innate immune system undergoes profound and long-lasting changes, the large-scale characterization of which may increase our biological understanding and help identify components with translational potential for guiding diagnosis and treatment decisions. With the ongoing technical development, proteomics will likely continue to provide increasing insights into complex biological processes and their implications for health and disease. Integrating proteomics with other omics data and utilizing multi-omics approaches have been demonstrated to give additional valuable insights into biological systems.
    Keywords:  complement system; inflammatory bowel disease; mass spectrometry; neutrophil extracellular traps; neutrophils; ontogeny; plasma; rheumatoid arthritis
    DOI:  https://doi.org/10.3389/fimmu.2023.1254948
  15. Talanta. 2023 Oct 17. pii: S0039-9140(23)01069-X. [Epub ahead of print]268(Pt 1): 125318
      Consistent retention time (tR) of metabolites is vital for identification in metabolomic analysis with ultrahigh-performance liquid-chromatography (UPLC). To minimize inter-experimental tR variations from the reversed-phase UPLC-MS, we developed an endogenous retention-index (endoRI) using in-sample straight-chain acylcarnitines with different chain-length (LC, C0-C26) without additives. The endoRI-corrections reduced the tR variations caused by the combined changes of mobile phases, gradients, flow-rates, elution time, columns and temperature from up to 5.1 min-0.2 min for most metabolites in a model metabolome consisting of 91 metabolites and multiple biological matrices including human serum, plasma, fecal, urine, A549 cells and rabbit liver extracts. The endoRI-corrections also reduced the inter-batch and inter-platform tR variations from 1.5 min to 0.15 min for 95 % of detected features in the above biological samples. We further established a quantitative model between tR and LC for predicting tR values of acylcarnitines when absent in samples. This makes it possible to compare metabolites' tR from different tR databases and the UPLC-based metabolomic data from different batches.
    Keywords:  Endogenous retention-index; Metabolic profiling; Metabonomics/metabolomics; Straight-chain acylcarnitines; Ultrahigh-performance liquid-chromatography-mass spectrometry
    DOI:  https://doi.org/10.1016/j.talanta.2023.125318
  16. Int J Hyperthermia. 2023 ;40(1): 2270654
      Cellular metabolic reprogramming is an important feature of malignant tumors. Metabolic reprogramming causes changes in the levels or types of specific metabolites inside and outside the cell, which affects tumorigenesis and progression by influencing gene expression, the cellular state, and the tumor microenvironment. During tumorigenesis, a series of changes in the glucose metabolism, fatty acid metabolism, amino acid metabolism, and cholesterol metabolism of tumor cells occur, which are involved in the process of cellular carcinogenesis and constitute part of the underlying mechanisms of tumor formation. Hyperthermia, as one of the main therapeutic tools for malignant tumors, has obvious effects on tumor cell metabolism. In this paper, we will combine the latest research progress in the field of cellular metabolic reprogramming and focus on the current experimental research and clinical treatment of hyperthermia in cellular metabolic reprogramming to discuss the feasibility of cellular metabolic reprogramming-related mechanisms guiding hyperthermia in malignant tumor treatment, so as to provide more ideas for hyperthermia to treat malignant tumors through the direction of cellular metabolic reprogramming.
    Keywords:  Tumor metabolism; combination therapy; hyperthermia; metabolic reprogramming
    DOI:  https://doi.org/10.1080/02656736.2023.2270654
  17. bioRxiv. 2023 Oct 03. pii: 2023.10.02.560544. [Epub ahead of print]
      Aging is one of the major risk factors for many chronic diseases, including diabetes, neuropathy, hypertension, cancer, and neurodegenerative diseases. However, the mechanism behind aging and how aging affects a variety of disease progression remains unknown. Recent research demonstrated the cytochrome P450 (CYP)-epoxide hydrolase (EH) metabolites of polyunsaturated fatty acids (PUFAs) play a critical role in the abovementioned age-associated diseases. Therefore, aging could affect the abovementioned chronic diseases by modulating CYP-EH PUFA metabolism. Unfortunately, investigating how aging affects CYP-EH metabolism in human and mammalian models poses significant challenges. In this regard, we will use C. elegans as a model organism to investigate the aging effects on CYP-EH metabolism of PUFA, owing to its long history of being used to study aging and its associated benefits of conducting aging research. This project will develop analytical tools to measure the endogenous levels of CYP-EH PUFA metabolites in C. elegans using state-of-the-art ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). These metabolites are very potent but present in low abundance. The dramatic increase in sensitivity in UPLC-MS/MS allows us to monitor these metabolites over the lifespan of C. elegans with minimum samples. Our results show that C. elegans produces similar CYP PUFA metabolites to mammals and humans using our SPE-UPLC-MS/MS method. We will also show that our method successfully determined the CYP-EH PUFA metabolites profile changes induced by the inhibition of C. elegans EH. The method developed from this project will significantly improve our understanding of the role of dietary PUFAs and associated metabolism on aging and neurodegeneration and will uncover new mechanisms of how aging affects neurodegeneration through the modulation of PUFA metabolic pathways.Graphical abstract:
    DOI:  https://doi.org/10.1101/2023.10.02.560544
  18. Int J Mol Sci. 2023 Oct 20. pii: 15396. [Epub ahead of print]24(20):
      Mass spectrometry has been an essential technique for the investigation of the metabolic pathways of living organisms since its appearance at the beginning of the 20th century. Due to its capability to resolve isotopically labeled species, it can be applied together with stable isotope tracers to reveal the transformation of particular biologically relevant molecules. However, low-resolution techniques, which were used for decades, had limited capabilities for untargeted metabolomics, especially when a large number of compounds are labelled simultaneously. Such untargeted studies may provide new information about metabolism and can be performed with high-resolution mass spectrometry. Here, we demonstrate the capabilities of high-resolution mass spectrometry to obtain insights on the metabolism of a model plant, Lepidium sativum, germinated in D2O and H218O-enriched media. In particular, we demonstrated that in vivo labeling with heavy water helps to identify if a compound is being synthesized at a particular stage of germination or if it originates from seed content, and tandem mass spectrometry allows us to highlight the substructures with incorporated isotope labels. Additionally, we found in vivo labeling useful to distinguish between isomeric compounds with identical fragmentation patterns due to the differences in their formation rates that can be compared by the extent of heavy atom incorporation.
    Keywords:  H/D exchange; garden cress; isotope exchange; mass spectrometry; plant metabolomics; stable isotope labeling
    DOI:  https://doi.org/10.3390/ijms242015396
  19. Proteomics. 2023 Oct 28. e2300088
      Due to their oftentimes ambiguous nature, phosphopeptide positional isomers can present challenges in bottom-up mass spectrometry-based workflows as search engine scores alone are often not enough to confidently distinguish them. Additional scoring algorithms can remedy this by providing confidence metrics in addition to these search results, reducing ambiguity. Here we describe challenges to interpreting phosphoproteomics data and review several different approaches to determine sites of phosphorylation for both data-dependent and data-independent acquisition-based workflows. Finally, we discuss open questions regarding neutral losses, gas-phase rearrangement, and false localization rate estimation experienced by both types of acquisition workflows and best practices for managing ambiguity in phosphosite determination. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/pmic.202300088
  20. Nat Commun. 2023 Oct 25. 14(1): 6777
      Reprogramming of amino acid metabolism, sustained by oncogenic signaling, is crucial for cancer cell survival under nutrient limitation. Here we discovered that missense mutant p53 oncoproteins stimulate de novo serine/glycine synthesis and essential amino acids intake, promoting breast cancer growth. Mechanistically, mutant p53, unlike the wild-type counterpart, induces the expression of serine-synthesis-pathway enzymes and L-type amino acid transporter 1 (LAT1)/CD98 heavy chain heterodimer. This effect is exacerbated by amino acid shortage, representing a mutant p53-dependent metabolic adaptive response. When cells suffer amino acids scarcity, mutant p53 protein is stabilized and induces metabolic alterations and an amino acid transcriptional program that sustain cancer cell proliferation. In patient-derived tumor organoids, pharmacological targeting of either serine-synthesis-pathway and LAT1-mediated transport synergizes with amino acid shortage in blunting mutant p53-dependent growth. These findings reveal vulnerabilities potentially exploitable for tackling breast tumors bearing missense TP53 mutations.
    DOI:  https://doi.org/10.1038/s41467-023-42458-1
  21. Prostaglandins Other Lipid Mediat. 2023 Oct 23. pii: S1098-8823(23)00086-2. [Epub ahead of print] 106789
      Urinary eicosanoid concentrations reflect inflammatory processes in multiple diseases and have been used as biomarkers of disease as well as for stratification in precision medicine. However, implementation of urinary eicosanoid profiling in large-scale analyses is restricted due to sample preparation limits. Here we demonstrate a single solid-phase extraction of 300µL urine in 96-well-format for prostaglandins, thromboxanes, isoprostanes, cysteinyl-leukotriene E4 and the linoleic acid-derived dihydroxy-octadecenoic acids (9,10- and 12,13-DiHOME). A simultaneous screening protocol was also developed for cortisol/cortisone and 7 exogenous steroids as well as 3 cyclooxygenase-inhibitors. Satisfactory performance for quantification of eicosanoids with a proper internal standard was demonstrated for intra-plate analyses (CV=8.5-15.1%) as well as for inter-plate (n=35) from multiple studies (CV=22.1-34.9%). Storage stability was evaluated at -20 °C, and polar tetranors evidenced a 50% decrease after 5 months, while the remaining eicosanoids evidenced no significant degradation. All eicosanoids were stable over 3.5-years in urine stored at -80°C. This method will facilitate the implementation of urinary eicosanoid quantification in large scale screening.
    Keywords:  COX-inhibitors; DiHOME; eicosanoid; inhaled corticosteroids; mass spectrometry; oral corticosteroids; solid-phase extraction; urine metabolites
    DOI:  https://doi.org/10.1016/j.prostaglandins.2023.106789