Deciphering cholangiocarcinoma heterogeneity and specific progenitor cell niche of extrahepatic cholangiocarcinoma at single-cell resolution

作者：Chunliang Liu, Xiang Wang, Erdong Liu, Yali Zong, Wenlong Yu, Youhai Jiang, Jianan Chen, Mingye Gu, Zhengyuan Meng, Jingfeng Li, Yang Liu, Yongjie Zhang, Jing Tang, Hongyang Wang, Jing Fu · 发表于：Journal of Hematology & Oncology · 年份：2025 · DOI：10.1186/s13045-025-01716-z · 被引用次数：14 · 研究领域：Single-cell and spatial transcriptomics、Cholangiocarcinoma and Gallbladder Cancer Studies、Cancer Cells and Metastasis

Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy, primarily comprising intrahepatic (iCCA) and extrahepatic (eCCA) subtypes. Reconciling the variability between iCCAs and eCCAs in clinical trials remains a challenge, largely due to the inadequate understanding of their shared and subtype-specific cellular heterogeneity. We aim to address this issue using single-cell and spatially resolved transcriptomic approaches. We performed comprehensive single-cell RNA sequencing (scRNA-seq) by profiling 109,071 single cells from 28 samples, including chronic biliary inflammatory conditions ( n = 7) and CCAs from different anatomical sites ( n = 21). Findings were validated using external multi-omics datasets, tissue microarray cohort, spatial RNA in situ sequencing, CCA patient-derived organoids (PDOs), and mouse models. iCCAs and eCCAs exhibited distinct tumor ecosystems, with notable differences in cellular composition, diversity, and abundance across various cell types. Non-malignant epithelial cells displayed divergent precancer hallmarks from different biliary sites, with inflammatory extrahepatic bile ducts exhibiting early hijacking of the gastrointestinal metaplastic process. We identified seven meta-programs within cancer cells, mapped into four major subtypes. This subtyping was validated using external CCA cohorts and PDO models, distinguishing patients based on clinical outcomes and drug vulnerabilities. Specifically, iCCAs were associated with a senescent progr...