Desterke Christophe, Francés Raquel, Monge Claudia, Fu Yuanji, Marchio Agnès, Pineau Pascal, Mata-Garrido Jorge
Faculté de Médecine du Kremlin Bicêtre, Université Paris-Saclay, INSERM UMRS-1310, Le Kremlin-Bicêtre, France.
Energy & Memory, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, Paris, France.
Biochem Biophys Rep. 2025 Feb 15;41:101949. doi: 10.1016/j.bbrep.2025.101949. eCollection 2025 Mar.
Intrahepatic cholangiocarcinoma (ICA) is a highly aggressive primary liver cancer, which originates from the epithelial cells of the bile ducts. The transcriptional profile of metabolic enzymes was investigated at both bulk and single-cell levels in tumor samples from distinct ICA cohorts. In a training cohort (TCGA consortium), 16 genes encoding for metabolic enzymes were found overexpressed in cases with poor survival. A computed metabolic gene expression score was significantly associated with worse ICA prognosis at the univariate level (overall survival [OS] log-rank p = 8.2e-4). After adjusting for Ishak fibrosis score and tumor staging, the metabolic expression remained an independent predictor of poor prognosis (multivariate OS log-rank p = 0.01). Seven genes encoding key enzymes (FH, MAT2B, PLOD2, PLOD1, PDE6D, ALDOC, and NT5DC3) were validated as markers of the proliferative subclass of ICA in the GSE32225 dataset, related to poor prognosis. The metabolic score was significantly different between the inflammatory and proliferative subclasses in the validation cohort (p < 2.2e-16). At the single-cell level, in the tumor microenvironment of 10 ICA patients, these seven enzymes were predominantly expressed by malignant cells. The single-cell metabolic score was thus higher in malignant cells. This study identifies a metabolic transcriptional program linked to poor prognosis in ICA, independent of fibrosis and tumor staging.
肝内胆管癌（ICA）是一种侵袭性很强的原发性肝癌，起源于胆管上皮细胞。在来自不同ICA队列的肿瘤样本中，从整体和单细胞水平研究了代谢酶的转录谱。在一个训练队列（TCGA联盟）中，发现16个编码代谢酶的基因在生存较差的病例中过表达。在单变量水平上，计算得出的代谢基因表达评分与ICA预后较差显著相关（总生存期[OS]对数秩p = 8.2e-4）。在调整Ishak纤维化评分和肿瘤分期后，代谢表达仍然是预后不良的独立预测因素（多变量OS对数秩p = 0.01）。在GSE32225数据集中，7个编码关键酶的基因（FH、MAT2B、PLOD2、PLOD1、PDE6D、ALDOC和NT5DC3）被验证为ICA增殖亚类的标志物，与预后不良相关。在验证队列中，炎症亚类和增殖亚类之间的代谢评分有显著差异（p < 2.2e-16）。在单细胞水平上，在10例ICA患者的肿瘤微环境中，这7种酶主要由恶性细胞表达。因此，恶性细胞中的单细胞代谢评分更高。本研究确定了一种与ICA预后不良相关的代谢转录程序，独立于纤维化和肿瘤分期。
