Function of mast cell and bile-cholangiocarcinoma interplay in cholangiocarcinoma microenvironment

作者：Anda Shi, Zengli Liu, Zhongqi Fan, Kangshuai Li, Xingkai Liu, Yongchang Tang, Jiaming Hu, Xingyong Li, Lizhuang Shu, Liming Zhao, Lingling Huang, Zhiyue Zhang, Guoyue Lv, Zongli Zhang, Yunfei Xu · 发表于：Gut · 年份：2024 · DOI：10.1136/gutjnl-2023-331715 · 被引用次数：23 · 研究领域：Mast cells and histamine、Cholangiocarcinoma and Gallbladder Cancer Studies、Chemokine receptors and signaling

Objective The correlation between cholangiocarcinoma (CCA) progression and bile is rarely studied. Here, we aimed to identify differential metabolites in benign and malignant bile ducts and elucidate the generation, function and degradation of bile metabolites. Design Differential metabolites in the bile from CCA and benign biliary stenosis were identified by metabonomics. Biliary molecules able to induce mast cell (MC) degranulation were revealed by in vitro and in vivo experiments, including liquid chromatography-mass spectrometry (MS)/MS and bioluminescence resonance energy transfer assays. Histamine (HA) receptor expression in CCA was mapped using a single-cell mRNA sequence. HA receptor functions were elucidated by patient-derived xenografts (PDX) in humanised mice and orthotopic models in MC-deficient mice. Genes involved in HA-induced proliferation were screened by CRISPR/Cas9. Results Bile HA was elevated in CCA and indicated poorer prognoses. Cancer-associated fibroblasts (CAFs)-derived stem cell factor (SCF) recruited MCs, and bile N,N-dimethyl-1,4-phenylenediamine (DMPD) stimulated MCs to release HA through G protein-coupled receptor subtype 2 (MRGPRX2)-Gαq signalling. Bile-induced MCs released platelet-derived growth factor subunit B (PDGF-B) and angiopoietin 1/2 (ANGPT1/2), which enhanced CCA angiogenesis and lymphangiogenesis. Histamine receptor H1 (HRH1) and HRH2 were predominantly expressed in CCA cells and CAFs, respectively. HA promoted CCA cell proliferatio...