Characterisation of Aberrant Metabolic Pathways in Hepatoblastoma Using Liquid Chromatography and Tandem Mass Spectrometry (LC-MS/MS)

Whitby, Alison; Pabla, Pardeep; Shastri, Bhoomi; Amugi, Laudina; Del Río-Álvarez, Álvaro; Kim, Dong-Hyun; Royo, Laura; Armengol, Carolina; Dandapani, Madhumita

Abstract

Hepatoblastoma (HB) is a rare childhood tumour with an evolving molecular landscape. We present the first comprehensive metabolomic analysis using untargeted and targeted liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-MS/MS) of paired tumour and non-tumour surgical samples in HB patients (n = 8 pairs). This study demonstrates that the metabolomic landscape of HB is distinct from that of non-tumour (NT) liver tissue, with 35 differentially abundant metabolites mapping onto pathways such as fatty acid transport, glycolysis, the tricarboxylic acid (TCA) cycle, branched-chain amino acid degradation and glutathione synthesis. Targeted metabolomics demonstrated reduced short-chain acylcarnitines and a relative accumulation of branched-chain amino acids. Medium- and long-chain acylcarnitines in HB were similar to those in NT. The metabolomic changes reported are consistent with previously reported transcriptomic data from tumour and non-tumour samples (49 out of 54 targets) as well as metabolomic data obtained using other techniques. Gene set enrichment analysis (GSEA) from RNAseq data (n = 32 paired HB and NT samples) demonstrated a downregulation of the carnitine metabolome and immunohistochemistry showed a reduction in CPT1a (n = 15 pairs), which transports fatty acids into the mitochondria, suggesting a lack of utilisation of long-chain fatty acids in HB. Thus, our findings suggest a reduced metabolic flux in HB which is corroborated at the gene expression and protein levels. Further work could yield novel insights and new therapeutic targets.

Citation

Whitby, A., Pabla, P., Shastri, B., Amugi, L., Del Río-Álvarez, Á., Kim, D.-H., Royo, L., Armengol, C., & Dandapani, M. (2023). Characterisation of Aberrant Metabolic Pathways in Hepatoblastoma Using Liquid Chromatography and Tandem Mass Spectrometry (LC-MS/MS). Cancers, 15(21), Article 5182. https://doi.org/10.3390/cancers15215182

• Journal Article Type: Article
• Acceptance Date: Oct 26, 2023
• Online Publication Date: Oct 28, 2023
• Publication Date: Nov 1, 2023
• Deposit Date: Nov 14, 2023
• Publicly Available Date: Nov 15, 2023
• Journal: Cancers
• Electronic ISSN: 2072-6694
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 21
• Article Number: 5182
• DOI: https://doi.org/10.3390/cancers15215182
• Keywords: hepatoblastoma; liquid chromatography and tandem mass spectrometry; metabolomics; acylcarnitine; fatty acid oxidation; carnitine palmitoyl transferase (CPT1)
• Public URL: https://nottingham-repository.worktribe.com/output/26811159
• Publisher URL: https://www.mdpi.com/2072-6694/15/21/5182
• Additional Information: Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).