Single-cell RNA-sequencing atlas reveals an MDK-dependent immunosuppressive environment in ErbB pathway-mutated gallbladder cancer

JOURNAL OF HEPATOLOGY

卷:75

Article

Zhang, Yijian^1,3,4,5  Zuo, Chunman⁶  Liu, Liguo^2,3,4,5  Hu, Yunping^1,3,4,5  Yang, Bo⁷  Qiu, Shimei^1,3,4,5  Li, Yang^2,3,4,5  Cao, Dongyan⁸  Ju, Zheng⁸  Ge, Jing⁶  Wang, Qiu⁶  Wang, Ting^1,3,4,5  Bai, Lu^1,3,4,5  Yang, Yang^2,3,4,5  Li, Guoqiang^2,3,4,5  Shao, Ziyu^1,3,4,5  Gao, Yuan^2,3,4,5  Li, Yongsheng^2,3,4,5  Bian, Rui^2,3,4,5  Miao, Huijie^2,3,4,5  Li, Lin^2,3,4,5  Li, Xuechuan^2,3,4,5  Jiang, Chengkai^2,3,4,5  Yan, Siyuan^2,3,4,5  Wang, Ziyi^2,3,4,5  Wang, Zeyu^2,3,4,5  Cui, Xuya^2,3,4,5  Huang, Wen^1,3,4,5  Xiang, Dongxi^2,3,4,5  Wang, Congjun⁹  Li, Qiyun¹⁰  Wu, Xiangsong^1,3,5  Gong, Wei^1,3,5  Liu, Yun^2,3,4,5  Shao, Rong^1,3,4,5,11  Liu, Fatao^1,3,4,5  Li, Maolan^1,3,5  Chen, Luonan^6,12,13,14  Liu, Yingbin^2,3,4,5 

[1] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp Affiliated, Dept Gen Surg, Shanghai 200092, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp Affiliated, Dept Biliary Pancreat Surg, Shanghai 200127, Peoples R China

[3] Shanghai Key Lab Biliary Tract Dis Res, Shanghai 200092, Peoples R China

[4] State Key Lab Oncogenes & Related Genes, Shanghai 200127, Peoples R China

[5] Shanghai Res Ctr Biliary Tract Dis, Shanghai 200092, Peoples R China

[6] Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, State Key Lab Cell Biol, Shanghai 200031, Peoples R China

[7] Wenzhou Med Univ, Affiliated Hosp 1, Dept Surg, Key Lab Diag & Treatment Severe Hepatopancreat Di, Wenzhou 325000, Peoples R China

[8] Novogene Bioinformat Inst, Beijing 100015, Peoples R China

[9] Shanghai Jiao Tong Univ, Peoples Hosp 1, Songjiang Cent Hosp Affiliated, Dept Gastroenterol Surg, Shanghai 201600, Peoples R China

[10] Jiangxi Prov Canc Hosp, Dept Abdominal Surg, Nanchang 330029, Jiangxi, Peoples R China

[11] Shanghai Jiao Tong Univ, Sch Med, Dept Pharmacol, Shanghai 200025, Peoples R China

[12] Univ Chinese Acad Sci, Chinese Acad Sci, Hangzhou Inst Adv Study, Key Lab Syst Hlth Sci Zhejiang Prov, Hangzhou 310024, Peoples R China

[13] Chinese Acad Sci, Ctr Excellence Anim Evolut & Genet, Kunming 650223, Yunnan, Peoples R China

[14] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

关键词: Gallbladder carcinoma;    Single-cell RNA-sequencing;    Tumor heterogene-ity;    ErbB pathway mutations;    Intercellular crosstalk;   

DOI  :  10.1016/j.jhep.2021.06.023

来源: Elsevier

【 摘 要 】

Background & Aims: Our previous genomic whole-exome sequencing (WES) data identified the key ErbB pathway mutations that play an essential role in regulating the malignancy of gallbladder cancer (GBC). Herein, we tested the hypothesis that individual cellular components of the tumor microenvironment (TME) in GBC function differentially to participate in ErbB pathway mutation-dependent tumor progression. Methods: We engaged single-cell RNA-sequencing to reveal transcriptomic heterogeneity and intercellular crosstalk from 13 human GBCs and adjacent normal tissues. In addition, we performed WES analysis to reveal the genomic variations related to tumor malignancy. A variety of bulk RNA-sequencing, immunohistochemical staining, immunofluorescence staining and functional experiments were employed to study the difference between tissues with or without ErbB pathway mutations. Results: We identified 16 cell types from a total of 114,927 cells, in which epithelial cells, M2 macrophages, and regulatory T cells were predominant in tumors with ErbB pathway mutations. Furthermore, epithelial cell subtype 1, 2 and 3 were mainly found in adenocarcinoma and subtype 4 was present in adenosquamous carcinoma. The tumors with ErbB pathway mutations harbored larger populations of epithelial cell subtype 1 and 2, and expressed higher levels of secreted midkine (MDK) than tumors without ErbB pathway mutations. Increased MDK resulted in an interaction with its receptor LRP1, which is expressed by tumor-infiltrating macrophages, and promoted immunosuppressive macrophage differentiation. Moreover, the crosstalk between macrophage-secreted CXCL10 and its receptor CXCR3 on regulatory T cells was induced in GBC with ErbB pathway mutations. Elevated MDK was correlated with poor overall survival in patients with GBC. Conclusions: This study has provided valuable insights into transcriptomic heterogeneity and the global cellular network in the TME, which coordinately functions to promote the progres-sion of GBC with ErbB pathway mutations; thus, unveiling novel cellular and molecular targets for cancer therapy. Lay summary: We employed single-cell RNA-sequencing and functional assays to uncover the transcriptomic heterogeneity and intercellular crosstalk present in gallbladder cancer. We found that ErbB pathway mutations reduced anti-cancer im-munity and led to cancer development. ErbB pathway mutations resulted in immunosuppressive macrophage differentiation and regulatory T cell activation, explaining the reduced anti-cancer immunity and worse overall survival observed in patients with these mutations. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

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