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

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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). Here, 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.We engaged single-cell RNA sequencing to reveal transcriptomic heterogeneity and intercellular crosstalk from 13 human GBC 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 ErbB pathway mutation and non-mutation tissues.We identified sixteen cell types from a total of 114,927 cells, in which epithelial cells, M2 macrophages, and Treg were predominant in ErbB pathway mutation tumors. Furthermore, epithelial cell subtype 1, 2 and 3 were mainly found in the adenocarcinoma and subtype 4 was present in adenosquamous carcinoma. The ErbB pathway mutation tumors harbored larger populations of epithelial cell subtype 1 and 2, and expressed higher levels of secreted midkine (MDK) than non-ErbB pathway mutation tumors. Increased MDK resulted in interaction with its receptor LRP1 expressed by tumor infiltrating macrophages and promoted immuno-suppressive macrophage differentiation. Moreover, the crosstalk between macrophage-secreted CXCL10 and its receptor CXCR3 on Tregs was induced in GBC with ErbB pathway mutations. Elevated MDK was correlated with poor overall survival of GBC patients.This study has provided valuable insights into transcriptomic heterogeneity and the global cellular network in the TME, which coordinately functions to promote the progression of GBC with ErbB pathway mutations; thus unveiling novel cellular and molecular targets for cancer therapy.We employed single-cell RNA sequencing and functional assays to reveal transcriptomic heterogeneity and intercellular crosstalk in GBC patients. GBC cancers were characterized with heterogenic cellular ecosystem in which the ErbB pathway mutations were associated with anti-cancer immunity and cancer development. Increased MDK from cancer cells of ErbB pathway mutation tumors resulted in interaction with its receptor LRP1 expressed by tumor infiltrating macrophages and promoted immuno-suppressive macrophage differentiation. In addition, the crosstalk between macrophage-secreted CXCL10 and its receptor CXCR3 on Tregs was induced in GBC with ErbB pathway mutations, which contributes to GBC progression.

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Authors: Yijian Zhang, Chunman Zuo, Liguo Liu, Yunping Hu, Bo Yang, Shimei Qiu, Yang Li, Dongyan Cao, Zheng Ju, Jing Ge, Qiu Wang, Ting Wang, Lu Bai, Yang Yang, Guoqiang Li, Ziyu Shao, Yuan Gao, Yongsheng Li, Rui Bian, Huijie Miao, Lin Li, Xuechuan Li, Chengkai Jiang, Siyuan Yan, Ziyi Wang, Zeyu Wang, Xuya Cui, Wen Huang, Dongxi Xiang, Congjun Wang, Qiyun Li, Xiangsong Wu, Wei Gong, Yun Liu, Rong Shao, Fatao Liu, Maolan Li, Luonan Chen, Yingbin Liu