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

PeerJ. 2022 Jan 4:10:e12568. doi: 10.7717/peerj.12568. eCollection 2022.

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.

Keywords: Amino acid metabolism; Cell line-derived xenograft; GC-MS; Malignant mesothelioma; Metabolomics.

Publication types

  • Randomized Controlled Trial, Veterinary
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System ASC
  • Animals
  • Biomarkers
  • Cell Line
  • Female
  • Heterografts
  • Isoleucine
  • Large Neutral Amino Acid-Transporter 1
  • Mesothelioma, Malignant*
  • Mice
  • Mice, Nude
  • Minor Histocompatibility Antigens

Substances

  • Amino Acid Transport System ASC
  • Biomarkers
  • Isoleucine
  • Large Neutral Amino Acid-Transporter 1
  • Minor Histocompatibility Antigens
  • SLC1A5 protein, human

Grants and funding

This work was supported by the National Natural Science Foundation of China (Grant numbers: 81672315 & 81302840 & 82072577), Key R&D Program Projects in Zhejiang Province (Grant number 2018C04009), Natural Science Foundation of Zhejiang Province of China (Grant numbers: LY21H160002 & LY20H280001), Excellent Youth Talent Program of Traditional Chinese medicine of Zhejiang province science and technology plan project (Grant number: 2017ZQ007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.