Metabolic profiling in cholangiocarcinoma

Abstract

Throughout this thesis, metabolic profiling using a global mass spectrometry-based approach was utilised to explore cholangiocarcinoma (CCA) metabolic signature in urine and serum. CCA is an aggressive disease with a poor prognosis. The geographical distribution of CCA cases is markedly uneven and it closely mirrors the prevalence of its predisposing risk factors. CCA is most commonly seen in Southeast Asia where liver fluke infection is endemic, whereas in Western countries it is a rare malignancy with an unknown aetiology in most cases. To date, a multi-disciplinary approach with multi-modal tools are often applied for the diagnosis of this complex disease. The primary aim of this thesis was to provide insights into the perturbed biological pathways underlying cholangiocarcinogenesis as a mean to identify metabolite biomarkers to improve CCA screening and diagnosis. The first four results chapters describes the urinary metabolome associated with liver fluke induced-CCA and sporadic CCA in patients from Thailand and the UK, respectively. Overall, CCA induces a metabolic profile change that can distinguish patients from healthy and control groups with various hepatobiliary pathologies. Dysregulation in acylcarnitine, bile acid, steroid and purine metabolism was characteristic of the CCA urinary metabolic signature in both populations. A panel of 10 metabolites (primarily acylcarnitine and steroid species) achieved a diagnostic accuracy of 93.4% and AUC value of 98.8% (CI= 96.3%-100%) in distinguishing CCA cases from healthy participants. Phenotypic disparities between the two distinct populations were primarily related to differences in dietary practices and body composition. Furthermore, regardless of the underlying aetiology, biological perturbations associated with the CCA urine metabolome signature appeared to be influenced by gut microbial community metabolism. Sporadic bile duct disease exhibited altered nucleotide metabolism, possibly indicating differences in mitochondrial energy production pathways related to differences in CCA underlying aetiology. Similarly, the serum metabolic patterns were differential in bile duct cancer, compared to healthy participants and individuals with benign and malignant hepatobiliary diseases. Impaired phospholipid homoeostases was particularly observed in CCA serum profiles, possibly suggesting influence of genetic variants that impair biliary phospholipid secretion on circulating lipids. A common metabotype, primarily indicative of inflammatory signature, was found to be associated with liver pathologies, both benign and malignant. Overall, it is possible to conclude that metabonomic profiling can identify disease-related metabotypes and may possibly contribute to uncovering novel candidate diagnostic biomarkers in CCA.