胆囊癌的多组学分析确定了与疾病进展相关的不同肿瘤微环境。

Multi-omic analysis of gallbladder cancer identifies distinct tumor microenvironments associated with disease progression.

作者信息

Zhou Tao, Wu Yanhong, Li Shuai, Qiu Xinyao, Liu Erdong, Xie Zhihua, Shi Xuebing, Zhang Yani, Ma Guosheng, Guo Wenbo, Wang Xiang, Wang Kaiting, Yao Xiaomeng, Hu Ji, Shen Siyun, Yang Shuai, Jiang Xiaoqing, Fu Jing, Wang Hongyang, Gu Jin, Chen Lei

机构信息

The International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.

MOE Key Laboratory of Bioinformatics, BNRIST Bioinformatics Division, Department of Automation, Tsinghua University, Beijing, China.

出版信息

Nat Genet. 2025 Jun 26. doi: 10.1038/s41588-025-02236-9.

DOI:10.1038/s41588-025-02236-9

PMID:40571730

Abstract

Gallbladder carcinoma (GBC) is the most aggressive biliary tract cancer and is associated with a high mortality rate. Treatment of GBC faces therapeutic challenges owing to the elusive nature of in situ drivers within the local tumor microenvironment that drive its progression. Here, we created a single-cell atlas of 1,117,245 cells and a mutational landscape from 102 patients, which unveiled spatial-temporal characterizations of cellular constitutions, spatial interplays and molecular functions, and generalized five local ecosystems stratifying clinical outcomes. An integrated epithelial program, AI-EPI, combined with spatial transcriptome analysis, revealed the concurrent localization of a highly malignant tumor subtype (GM16) and AREG T cell, B cell, dendritic cell and macrophage subtypes within the pro-metastatic niche of primary adenocarcinomas. In vitro and in vivo experiments suggest that in addition to promoting metastasis, AREG facilitates CXCL5 expression in tumor cells through EGFR-pERK-EGR1 signaling, leading to increased neutrophil infiltration and impeding the effectiveness of immunotherapy. Our study provides a spatial-temporal landscape of the GBC microenvironment and sheds light on potential strategies for preventing immunotherapy resistance.

摘要

胆囊癌（GBC）是最具侵袭性的胆道癌，死亡率很高。由于驱动其进展的局部肿瘤微环境中原位驱动因素难以捉摸，GBC的治疗面临着挑战。在这里，我们创建了一个包含1117245个细胞的单细胞图谱和来自102名患者的突变图谱，揭示了细胞组成、空间相互作用和分子功能的时空特征，并归纳出了五种分层临床结果的局部生态系统。一个整合的上皮程序AI-EPI，结合空间转录组分析，揭示了原发性腺癌转移前生态位内高度恶性肿瘤亚型（GM16）与AREG T细胞、B细胞、树突状细胞和巨噬细胞亚型的同时定位。体外和体内实验表明，除了促进转移外，AREG还通过EGFR-pERK-EGR1信号通路促进肿瘤细胞中CXCL5的表达，导致中性粒细胞浸润增加，并阻碍免疫治疗的效果。我们的研究提供了GBC微环境的时空图谱，并为预防免疫治疗耐药性的潜在策略提供了线索。