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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Multi-omics profiling reveals cholic acid-mediated immunosuppression driven by peritumoral ductular reactions in
Qianhui Xu1, Hang Chen2, Ganggang Wang2
1Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China; Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract:
Hepatocellular carcinoma remains a leading cause of cancer mortality worldwide, with peritumoral microenvironment interactions playing a critical role in disease progression. This multi-omics study employed artificial intelligence-pathology, single-nucleus multi-omics, spatial transcriptomics, and metabolomics to characterize peritumoral ductular reactions. Ductular reaction scores strongly predicted poor clinical outcomes and correlated with cirrhosis severity. We identified three functionally distinct cholangiocyte subpopulations, with Small_duct_type_Cho exhibiting robust fibroblast interactions that promote stromal remodeling. Metabolomic profiling revealed tumor margin enrichment of cholic acid, which induced CD8+ T cell dysfunction via NR1H4-dependent PD1 upregulation. Importantly, NR1H4 inhibition synergized with anti-PD1 therapy in murine models, significantly suppressing tumor growth. These results position ductular reactions as both a prognostic biomarker and therapeutic target, with cholic acid/NR1H4 pathway inhibition representing a promising immunotherapeutic strategy for hepatocellular carcinoma patients.
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