Linsey E. Jackson , Jennifer L. Tomlinson , Roberto Alva-Ruiz , Lindsey A. Gregory , Seul Kee Byeon , Amro M. Abdelrahman , Dong-Gi Mun , Caroline W. Grant , Zachary C. Fogarty , Chen Wang , Lewis R. Roberts , Rondell P. Graham , Mitesh J. Borad , Sumera I. Ilyas , Gregory J. Gores , Akhilesh Pandey , Arjun P. Athreya , Rory L. Smoot
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引用次数: 0
Abstract
Background & Aims
Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA.
Methods
Leveraging a biospecimen collection, including samples from patients with digestive diseases and normal controls, global serum metabolomic and lipidomic profiling was performed on 213 patients with CCA and 98 healthy controls. The CCA cohort of patients included representation of intrahepatic, perihilar, and distal CCA tumours. Metabolome-wide association studies utilizing multivariable linear regression were used to perform case–control comparisons, followed by pathway enrichment analysis, CCA subtype analysis, and disease stage analysis. The impact of biliary obstruction was evaluated by repeating analyses in subsets of patients only with normal bilirubin levels.
Results
Of the 420 metabolites that discriminated patients with CCA from controls, decreased abundance of cysteine-glutathione disulfide was most closely associated with CCA. Additional conjugated bile acid species were found in increased abundance even in the absence of clinically relevant biliary obstruction denoted by elevated serum bilirubin levels. Pathway enrichment analysis also revealed alterations in caffeine metabolism and mitochondrial redox-associated pathways in the serum of patients with CCA.
Conclusions
The presented metabolomic and lipidomic profiling demonstrated multiple alterations in the serum of patients with CCA. These exploratory data highlight novel metabolic pathways in CCA and support future work in therapeutic targeting of these pathways and the development of a precision biomarker panel for diagnosis.
Impact and implications
Cholangiocarcinoma (CCA) is a highly lethal hepatobiliary cancer with limited treatment response, highlighting the need for a better understanding of the disease biology. Using a global metabolomics and lipidomics platform, we characterized distinct changes in the serum of 213 patients with CCA compared with healthy controls. The results of this study elucidate novel metabolic pathways in CCA. These findings benefit stakeholders in both the clinical and research realms by providing a foundation for improved disease diagnostics and identifying novel targets for therapeutic design.
背景& 目的代谢组学和脂质组学分析为深入了解新生物学提供了机会。胆管癌(CCA)仍然是一种致死率很高的癌症,对全身、靶向和免疫治疗方法的反应有限。本研究利用全球代谢组学和脂质组学平台,旨在发现和描述CCA患者的代谢组变异和相关通路失调。方法利用生物样本收集(包括消化系统疾病患者和正常对照组的样本),对213名CCA患者和98名健康对照组进行了全球血清代谢组学和脂质组学分析。CCA患者群包括肝内、肝周和远端CCA肿瘤。利用多变量线性回归的全代谢组关联研究进行了病例对照比较,随后进行了通路富集分析、CCA 亚型分析和疾病分期分析。结果 在区分 CCA 患者和对照组的 420 种代谢物中,半胱氨酸-谷胱甘肽二硫化物丰度的降低与 CCA 的关系最为密切。即使在血清胆红素水平升高、没有临床相关胆道梗阻的情况下,也能发现其他共轭胆汁酸种类的丰度增加。通路富集分析还揭示了 CCA 患者血清中咖啡因代谢和线粒体氧化还原相关通路的改变。这些探索性数据突显了 CCA 中的新型代谢通路,为今后针对这些通路进行治疗和开发用于诊断的精准生物标记物面板提供了支持。 影响和意义胆管癌(CCA)是一种致死率很高的肝胆癌,但治疗效果有限,因此需要更好地了解这种疾病的生物学特性。利用全球代谢组学和脂质组学平台,我们对 213 名 CCA 患者与健康对照组相比血清中的明显变化进行了表征。这项研究的结果阐明了 CCA 的新代谢途径。这些发现为改进疾病诊断和确定治疗设计的新靶点奠定了基础,使临床和研究领域的相关人员受益匪浅。
期刊介绍:
JHEP Reports is an open access journal that is affiliated with the European Association for the Study of the Liver (EASL). It serves as a companion journal to the highly respected Journal of Hepatology.
The primary objective of JHEP Reports is to publish original papers and reviews that contribute to the advancement of knowledge in the field of liver diseases. The journal covers a wide range of topics, including basic, translational, and clinical research. It also focuses on global issues in hepatology, with particular emphasis on areas such as clinical trials, novel diagnostics, precision medicine and therapeutics, cancer research, cellular and molecular studies, artificial intelligence, microbiome research, epidemiology, and cutting-edge technologies.
In summary, JHEP Reports is dedicated to promoting scientific discoveries and innovations in liver diseases through the publication of high-quality research papers and reviews covering various aspects of hepatology.