间质细胞
免疫系统
胆囊癌
胆囊
癌症研究
医学
肿瘤微环境
生物
免疫学
癌症
病理
内科学
遗传学
作者
Huisi He,Shuzhen Chen,Yong Yu,Zhecai Fan,You–Wen Qian,Yaping Dong,Yuting Song,Caiming Zhong,Sun Xiaojuan,Qiqi Cao,Shiyao Li,Weihan Huang,Wenxin Li,Mingzhu Zhuang,Jinxian Yang,Xianming Wang,Jiaqian Wang,Dongfang Wu,Hongyang Wang,Wen Wen
出处
期刊:Gut
[BMJ]
日期:2024-05-06
卷期号:: gutjnl-331773
被引量:2
标识
DOI:10.1136/gutjnl-2023-331773
摘要
Objective Elucidating complex ecosystems and molecular features of gallbladder cancer (GBC) and benign gallbladder diseases is pivotal to proactive cancer prevention and optimal therapeutic intervention. Design We performed single-cell transcriptome analysis on 230 737 cells from 15 GBCs, 4 cholecystitis samples, 3 gallbladder polyps, 5 gallbladder adenomas and 16 adjacent normal tissues. Findings were validated through large-scale histological assays, digital spatial profiler multiplexed immunofluorescence (GeoMx), etc. Further molecular mechanism was demonstrated with in vitro and in vivo studies. Results The cell atlas unveiled an altered immune landscape across different pathological states of gallbladder diseases. GBC featured a more suppressive immune microenvironment with distinct T-cell proliferation patterns and macrophage attributions in different GBC subtypes. Notably, mutual exclusivity between stromal and immune cells was identified and remarkable stromal ecosystem (SC) heterogeneity during GBC progression was unveiled. Specifically, SC1 demonstrated active interaction between Fibro-iCAF and Endo-Tip cells, correlating with poor prognosis. Moreover, epithelium genetic variations within adenocarcinoma (AC) indicated an evolutionary similarity between adenoma and AC. Importantly, our study identified elevated olfactomedin 4 (OLFM4) in epithelial cells as a central player in GBC progression. OLFM4 was related to T-cell malfunction and tumour-associated macrophage infiltration, leading to a worse prognosis in GBC. Further investigations revealed that OLFM4 upregulated programmed death-ligand 1 (PD-L1) expression through the MAPK-AP1 axis, facilitating tumour cell immune evasion. Conclusion These findings offer a valuable resource for understanding the pathogenesis of gallbladder diseases and indicate OLFM4 as a potential biomarker and therapeutic target for GBC.
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