A single-cell multi-omic atlas of extrahepatic cholangiocarcinoma progression with ST6GAL1-enriched preinvasive states.

作者：Siming Kong, Rongyan Yao, 项灿宏, Hui Bai · 发表于：Journal of Clinical Oncology · 年份：2026 · DOI：10.1200/jco.2026.44.19_suppl.176 · 研究领域：Cholangiocarcinoma and Gallbladder Cancer Studies、Single-cell and spatial transcriptomics、Liver Diseases and Immunity

176 Background: Extrahepatic cholangiocarcinoma (eCCA) is frequently diagnosed at advanced stages, limiting opportunities for early intervention. Chronic biliary inflammation is a recognized risk context, however, the cellular and epigenetic changes linking inflammatory injury to preinvasive lesions and invasive eCCA remain incompletely defined. We generated a stage-resolved single-cell multi-omic atlas to characterize this progression and prioritize candidates associated with preinvasive remodeling. Methods: Fresh human biliary tissues spanning the disease continuum (normal bile duct (n=2), inflammatory lesions (n=7), intraductal papillary neoplasm of the bile duct (IPNB; n=3), and invasive eCCA including perihilar (n=8) and distal (n=4) subtypes) were profiled using integrated single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq). Analyses included cross-sample integration, cell-type annotation, epithelial trajectory inference, copy-number inference, chromatin accessibility dynamics, and cross-modal candidate prioritization. Candidate genes were further evaluated using donor-level pseudo-bulk expression profiling across pathological stages. Results: We resolved an epithelial progression continuum characterized by increasing transcriptional reprogramming and genomic instability, with copy-number abnormalities detectable before overt invasion. IPNB exhibited substantial epithelial heterogeneity, consistent with branching preinvasive states. Cross...