Metabolomics, which is the profiling of metabolites in biofluids, cells and tissues, is routinely applied as a tool for biomarker discovery. Owing to innovative developments in informatics and ...analytical technologies, and the integration of orthogonal biological approaches, it is now possible to expand metabolomic analyses to understand the systems-level effects of metabolites. Moreover, because of the inherent sensitivity of metabolomics, subtle alterations in biological pathways can be detected to provide insight into the mechanisms that underlie various physiological conditions and aberrant processes, including diseases.
Ferroptosis has emerged as a promising target for colorectal cancer (CRC) treatment. Although disrupting glutathione metabolism is the primary strategy for ferroptosis induction, additional key ...pathways link ferroptosis to CRC pathogenesis. Here, we discuss arachidonic acid (AA), energy metabolism, AMP-activated protein kinase (AMPK), phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR), and Hippo signaling, summarize key findings, and propose new conceptual avenues for CRC treatment.
Bacterial biofilms in the colon alter the host tissue microenvironment. A role for biofilms in colon cancer metabolism has been suggested but to date has not been evaluated. Using metabolomics, we ...investigated the metabolic influence that microbial biofilms have on colon tissues and the related occurrence of cancer. Patient-matched colon cancers and histologically normal tissues, with or without biofilms, were examined. We show the upregulation of polyamine metabolites in tissues from cancer hosts with significant enhancement of N1, N12-diacetylspermine in both biofilm-positive cancer and normal tissues. Antibiotic treatment, which cleared biofilms, decreased N1, N12-diacetylspermine levels to those seen in biofilm-negative tissues, indicating that host cancer and bacterial biofilm structures contribute to the polyamine metabolite pool. These results show that colonic mucosal biofilms alter the cancer metabolome to produce a regulator of cellular proliferation and colon cancer growth potentially affecting cancer development and progression.
Display omitted
•Colonic mucosal biofilms alter the cancer metabolome•N1, N12-diacetylspermine was significantly upregulated in tissues with biofilms•Biofilms create conditions conducive to oncogenic transformation in colon cells•Global isotope metabolomics reveals the metabolite fate of N1, N12-diacetylspermine
Johnson et al. examine the metabolomics of bacterial communities called biofilms and human colon cancers. The host and bacterial polyamine metabolites are proposed to act together to promote biofilm formation and cancer growth, creating conditions conducive for normal to cancer cell transformation.
Bioinformatics: The Next Frontier of Metabolomics Johnson, Caroline H; Ivanisevic, Julijana; Benton, H. Paul ...
Analytical chemistry (Washington),
01/2015, Letnik:
87, Številka:
1
Journal Article
The gut microbiome plays an important role in systemic inflammation and immune response. Microbes can translocate and reside in tumour niches. However, it is unclear how the intratumour microbiome ...affects immunity in human cancer. The purpose of this study was to investigate the association between intratumour bacteria, infiltrating CD8+ T cells and patient survival in cutaneous melanoma.
Using The Cancer Genome Altas's cutaneous melanoma RNA sequencing data, levels of intratumour bacteria and infiltrating CD8+ T cells were determined. Correlation between intratumour bacteria and infiltrating CD8+ T cells or chemokine gene expression and survival analysis of infiltrating CD8+ T cells and Lachnoclostridium in cutaneous melanoma were performed.
Patients with low levels of CD8+ T cells have significantly shorter survival than those with high levels. The adjusted hazard ratio was 1.57 (low vs high) (95% confidence interval: 1.17–2.10, p = 0.002). Intratumour bacteria of the Lachnoclostridium genus ranked top in a positive association with infiltrating CD8+ T cells (correlation coefficient = 0.38, p = 9.4 × 10−14), followed by Gelidibacter (0.31, p = 1.13 × 10−9), Flammeovirga (0.29, p = 1.96 × 10−8) and Acinetobacter (0.28, p = 8.94 × 10−8). These intratumour genera positively correlated with chemokine CXCL9, CXCL10 and CCL5 expression. The high Lachnoclostridium load significantly reduced the mortality risk (p = 0.0003). However, no statistically significant correlation was observed between intratumour Lachnoclostridium abundance and the levels of either NK, B or CD4+ T cells.
Intratumour-residing gut microbiota could modulate chemokine levels and affect CD8+ T-cell infiltration, consequently influencing patient survival in cutaneous melanoma. Manipulating the intratumour gut microbiome may benefit patient outcomes for those undergoing immunotherapy.
•High infiltration of cytotoxic CD8+ T cells benefits outcomes of patients with melanoma.•Intratumour bacteria are associated with the infiltration of cytotoxic CD8+ T cells.•Intratumour bacteria might affect the chemokines for migration of CD8+ T cells.•The high Lachnoclostridium load in tumour significantly reduced the mortality risk.
Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide and is characterised by frequently mutated genes, such as APC, TP53, KRAS and BRAF. The current treatment options of ...chemotherapy, radiation therapy and surgery are met with challenges such as cancer recurrence, drug resistance, and overt toxicity. CRC therapies exert their efficacy against cancer cells by activating biological pathways that contribute to various forms of regulated cell death (RCD). In 2012, ferroptosis was discovered as an iron-dependent and lipid peroxide-driven form of RCD. Recent studies suggest that therapies which target ferroptosis are promising treatment strategies for CRC. However, a greater understanding of the mechanisms of ferroptosis initiation, propagation, and resistance in CRC is needed. This review provides an overview of recent research in ferroptosis and its potential role as a therapeutic target in CRC. We also propose future research directions that could help to enhance our understanding of ferroptosis in CRC.
Untargeted metabolomics provides a comprehensive platform for identifying metabolites whose levels are altered between two or more populations. By using liquid chromatography quadrupole ...time-of-flight mass spectrometry (LC-Q-TOF-MS), hundreds to thousands of peaks with a unique m/z ratio and retention time are routinely detected from most biological samples in an untargeted profiling experiment. Each peak, termed a metabolomic feature, can be characterized on the basis of its accurate mass, retention time and tandem mass spectral fragmentation pattern. Here a seven-step protocol is suggested for such a characterization by using the METLIN metabolite database. The protocol starts from untargeted metabolomic LC-Q-TOF-MS data that have been analyzed with the bioinformatics program XCMS, and it describes a strategy for selecting interesting features as well as performing subsequent targeted tandem MS. The seven steps described will require 2-4 h to complete per feature, depending on the compound.
The metabolome is a data‐rich source of information concerning all the low‐molecular‐weight metabolites in a biofluid, which can indicate early biological changes to the host due to perturbations in ...metabolic pathways. Major changes can be seen after minor stimuli, which make it a valuable target for analysis. Due to the diverse and sensitive nature of the metabolome, studies must be designed in a manner to maintain consistency, reduce variation between subjects, and optimize information recovery. Technological advancements in experimental design, mouse models and instrumentation have aided in this effort. Metabolomics has the ultimate potential to be valuable in a clinical setting where it could be used for early diagnosis of a disease and as a predictor of treatment response and survival. During drug treatment, the metabolic status of an individual could be monitored and used to indicate possible toxic effects. Metabolomics therefore has great potential for improving diagnosis, treatment and aftercare of disease.
J. Cell. Physiol. 227: 2975–2981, 2012. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.
•Comprehensive review of research studies on metabolomics of PFAS exposures in humans.•PFAS exposures are associated with disruption of amino acid, energy and lipid metabolism.•Metabolic alterations ...associated with PFAS are implicated in cardiometabolic health.•Research needs include prospective design, standardized reporting, and risk of bias.
To summarize the application of non-targeted metabolomics in epidemiological studies that assessed metabolite and metabolic pathway alterations associated with per- and polyfluoroalkyl substances (PFAS) exposure.
Eleven human studies published before April 1st, 2021 were identified through database searches (PubMed, Dimensions, Web of Science Core Collection, Embase, Scopus), and citation chaining (Citationchaser). The sample sizes of these studies ranged from 40 to 965, involving children and adolescents (n = 3), non-pregnant adults (n = 5), or pregnant women (n = 3). High-resolution liquid chromatography–mass spectrometry was the primary analytical platform to measure both PFAS and metabolome. PFAS were measured in either plasma (n = 6) or serum (n = 5), while metabolomic profiles were assessed using plasma (n = 6), serum (n = 4), or urine (n = 1). Four types of PFAS (perfluorooctane sulfonate(n = 11), perfluorooctanoic acid (n = 10), perfluorohexane sulfonate (n = 9), perfluorononanoic acid (n = 5)) and PFAS mixtures (n = 7) were the most studied. We found that alterations to tryptophan metabolism and the urea cycle were most reported PFAS-associated metabolomic signatures. Numerous lipid metabolites were also suggested to be associated with PFAS exposure, especially key metabolites in glycerophospholipid metabolism which is critical for biological membrane functions, and fatty acids and carnitines which are relevant to the energy supply pathway of fatty acid oxidation. Other important metabolome changes reported included the tricarboxylic acid (TCA) cycle regarding energy generation, and purine and pyrimidine metabolism in cellular energy systems.
There is growing interest in using non-targeted metabolomics to study the human physiological changes associated with PFAS exposure. Multiple PFAS were reported to be associated with alterations in amino acid and lipid metabolism, but these results are driven by one predominant type of pathway analysis thus require further confirmation. Standardizing research methods and reporting are recommended to facilitate result comparison. Future studies should consider potential differences in study methodology, use of prospective design, and influence from confounding bias and measurement errors.
Reproducibility, traceability, and transparency have been long-standing issues for metabolomics data analysis. Multiple tools have been developed, but limitations still exist. Here, we present the ...tidyMass project ( https://www.tidymass.org/ ), a comprehensive R-based computational framework that can achieve the traceable, shareable, and reproducible workflow needs of data processing and analysis for LC-MS-based untargeted metabolomics. TidyMass is an ecosystem of R packages that share an underlying design philosophy, grammar, and data structure, which provides a comprehensive, reproducible, and object-oriented computational framework. The modular architecture makes tidyMass a highly flexible and extensible tool, which other users can improve and integrate with other tools to customize their own pipeline.
PDF
