Metabolomics of a cell line-derived xenograft model reveals circulating metabolic signatures for malignant mesothelioma

Our plain-English summary of Metabolomics of a cell line-derived xenograft model reveals circulating metabolic signatures for malignant mesothelioma, by Y. Gao, Z. Dai, C. Yang, et al (PeerJ, 2022).

The study

• Authors: Y. Gao, Z. Dai, C. Yang, D. Wang, Z. Guo, W. Mao, Z. Chen
• Journal: PeerJ
• Published: 2022;10:e12568
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) is a rare and highly aggressive cancer. Despite advances in multidisciplinary treatments for cancer, the prognosis for MM remains poor with no effective diagnostic biomarkers currently available. The aim of this study was to identify plasma metabolic biomarkers for better MM diagnosis and prognosis by use of a MM cell line-derived xenograft (CDX) model.

Methods: The MM CDX model was confirmed by hematoxylin and eosin staining and immunohistochemistry. Twenty female nude mice were randomly divided into two groups, 10 for the MM CDX model and 10 controls. Plasma samples were collected two weeks after tumor cell implantation. Gas chromatography-mass spectrometry analysis was conducted. Both univariate and multivariate statistics were used to select potential metabolic biomarkers. Hierarchical clustering analysis, metabolic pathway analysis, and receiver operating characteristic (ROC) analysis were performed. Additionally, bioinformatics analysis was used to investigate differential genes between tumor and normal tissues, and survival-associated genes.

Results: The MM CDX model was successfully established. With VIP > 1.0 and P-value < 0.05, a total of 23 differential metabolites were annotated, in which isoleucine, 5-dihydrocortisol, and indole-3-acetamide had the highest diagnostic values based on ROC analysis. These were mainly enriched in pathways for starch and sucrose metabolism, pentose and glucuronate interconversions, galactose metabolism, steroid hormone biosynthesis, as well as phenylalanine, tyrosine and tryptophan biosynthesis. Further, down-regulation was observed for amino acids, especially isoleucine, which is consistent with up-regulation of amino acid transporter genes SLC7A5 and SLC1A3 in MM. Overall survival was also negatively associated with SLC1A5, SLC7A5, and SLC1A3.

Conclusion: We found several altered plasma metabolites in the MM CDX model. The importance of specific metabolic pathways, for example amino acid metabolism, is herein highlighted, although further investigation is warranted.

©2022 Gao et al.

In plain English

This was mainly a mouse study; it did not study asbestos exposure. The authors injected a human malignant mesothelioma cell line (Ren cells) under the flank skin of 10 female nude mice and left 10 other mice untreated. Two weeks later they measured small molecules (metabolites) in the mice's blood plasma. The authors reported 23 metabolites that differed between the groups: 6 were higher and 17 lower in the tumor-bearing mice. Isoleucine and 5-dihydrocortisol best separated the groups (area under the curve 0.860 each). Most amino acids, including isoleucine, were lower in tumor-bearing mice; tyrosine was the exception. The authors also analyzed public patient gene data and stained patient tumor tissue. In public data on 86 patients, higher expression of three amino acid transporter genes was associated with worse survival. The hazard ratios were 1.70 for SLC1A5 (95% confidence interval 1.06 to 2.72), 2.35 for SLC7A5 (1.45 to 3.82) and 2.21 for SLC1A3 (1.38 to 3.56). The authors said their proposed explanations remain hypothetical and need further study. They concluded the findings may help in diagnosing mesothelioma and predicting its course.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (mouse cell line-derived xenograft model) with plasma metabolomics by gas chromatography-mass spectrometry. It also included bioinformatics analysis of public human gene expression and survival datasets and immunohistochemistry on human mesothelioma tissue.
• Who was studied: 20 female BALB/c nude mice, 4 weeks old, studied at Zhejiang Cancer Hospital, Hangzhou, China: 10 given xenografts and 10 untreated controls. The human components were:
• a public gene array dataset (GSE51024) of 55 mesothelioma tumor samples, 41 of them with paired normal tissue;
• TCGA gene expression and survival data for 86 mesothelioma patients;
• tumor specimens from mesothelioma patients, examined by immunohistochemistry (number not given).
  Study dates were not given.
• Exposure: No asbestos or fiber exposure was studied. Mice were injected under the skin of the flank with a human malignant mesothelioma cell line (Ren cells); control mice received no treatment.
• Main results:
  • The tumors grown in the mice were biphasic malignant mesothelioma on staining, and immunohistochemistry was consistent with mesothelioma.
  • 23 plasma metabolites differed between xenograft mice and controls: 6 higher and 17 lower in the xenograft mice.
  • The differential metabolites were linked to 19 enriched metabolic pathways.
  • Six metabolites best distinguished xenograft mice from controls, measured by area under the ROC curve (AUC): isoleucine (0.860), 5-dihydrocortisol (0.860), guanosine (0.850), indole-3-acetamide (0.850), trehalose-6-phosphate (0.840) and diglycerol (0.830). Indole-3-acetamide and diglycerol were higher in xenograft mice; the other four were lower.
  • In plasma of xenograft mice, most detected amino acids were lower, including isoleucine, valine and proline; tyrosine was the exception.
  • In TCGA data on mesothelioma patients, higher expression of three amino acid transporter genes was associated with worse survival. The hazard ratios were SLC1A5 1.70 (95% CI 1.06 to 2.72), SLC7A5 2.35 (1.45 to 3.82) and SLC1A3 2.21 (1.38 to 3.56).
  • In the GEO dataset, SLC7A5 and SLC1A3 gene expression was higher and SLC1A5 lower in mesothelioma tissue than in control tissue.
  • Immunohistochemistry showed SLC1A5 and SLC7A5 expression in tumor specimens from both mouse xenografts and mesothelioma patients.
• The authors' conclusion: The authors concluded that the mechanisms they proposed remain hypothetical. They also concluded that the findings may help diagnosis and prognosis of malignant mesothelioma and may point to therapeutic targets.
• Limitations the authors state:
  • The authors stated that the mechanisms they proposed to explain the metabolite changes are hypothetical and need further investigation.
  • The authors noted that the lower SLC1A5 expression they found disagrees with other studies and needs more research.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Prognosis, Biomarker, Immunohistochemistry, P-Value, Overall Survival.

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