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

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

doi:10.1136/gutjnl-2023-331715

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

Gut. 2024 Mar 8:gutjnl-2023-331715. doi: 10.1136/gutjnl-2023-331715. Online ahead of print.

Authors

Anda Shi^#¹, Zengli Liu^#^{1

2}, Zhongqi Fan^#³, Kangshuai Li¹, Xingkai Liu³, Yongchang Tang¹, Jiaming Hu¹, Xingyong Li⁴, Lizhuang Shu¹, Liming Zhao¹, Lingling Huang⁵, Zhiyue Zhang⁵, Guoyue Lv⁶, Zongli Zhang⁷, Yunfei Xu⁷

Affiliations

¹ Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
² Department of General Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
³ Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China.
⁴ Department of Hepatobiliary Surgery, Shandong University, Jinan, Shandong, China.
⁵ Department of Pharmaceutics, Shandong University, Jinan, Shandong, China.
⁶ Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China xuyunfei1988@126.com lvgy@jlu.edu.cn zzlzzl1900@163.com.
⁷ Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China xuyunfei1988@126.com lvgy@jlu.edu.cn zzlzzl1900@163.com.

^# Contributed equally.

PMID: 38458750
DOI: 10.1136/gutjnl-2023-331715

Abstract

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 proliferation by activating HRH1-Gαq signalling and hastened CAFs to secrete hepatocyte growth factor by stimulating HRH2-Gαs signalling. Solute carrier family 22 member 3 (SLC22A3) inhibited HA-induced CCA proliferation by importing bile HA into cells for degradation, and SLC22A3 deletion resulted in HA accumulation.

Conclusion: Bile HA is released from MCs through DMPD stimulation and degraded via SLC22A3 import. Different HA receptors exhibit a distinct expression profile in CCA and produce different oncogenic effects. MCs promote CCA progression in a CCA-bile interplay pattern.

Keywords: ANGIOGENESIS; BILE; CHOLANGIOCARCINOMA; HISTAMINE; MAST CELLS.