Single-cell analysis defines LGALS1+fibroblasts that promote proliferation and migration of intrahepatic cholangiocarcinoma  

作　　者：Qiqi Cao Jinxian Yang Lixuan Jiang Zhao Yang Zhecai Fan Shuzhen Chen Sibo Zhu Lei Yin Hongyang Wang Wen Wen 

机构地区：[1]Third Affiliated Hospital of Naval Medical University,National Center for Liver Cancer,Shanghai 200438,China [2]International Cooperation Laboratory on Signal Transduction,Eastern Hepatobiliary Surgery Hospital,Naval Medical University,Shanghai 200438,China [3]Department of Oncology,971 Hospital of PLA Navy,Qingdao 266071,China [4]Department of Hepatobiliary Surgery,Third Affiliated Hospital of Naval Medical University,Shanghai 200438,China [5]Ministry of Education(MOE)Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer,Naval Medical University,Shanghai 200438,China [6]MOE Key Laboratory of Contemporary Anthropology,School of Life Sciences,Fudan University,Shanghai 200438,China [7]Fudan University Shanghai Cancer Center,Shanghai 200032,China

出　　处：《Journal of Molecular Cell Biology》2024年第6期14-27,共14页分子细胞生物学报(英文版)

基　　金：National Natural Science Foundation of China(82072600,82173146,81830054,81988101,and 91859205);Plan of the Shanghai Municipal Health Commission(2022XD036).

摘　　要：The incidence rate of intrahepatic cholangiocarcinoma(ICC),which has a poor prognosis,is rapidly increasing.To investigate the intratumor heterogeneity in ICC,we analyzed single-cell RNA sequencing data from the primary tumor and adjacent normal tissues of 14 treatment-naïve patients.We identified 10 major cell types,along with 45 subclusters of cells.Notably,we identified a fibroblast cluster,Fibroblast_LUM+,which was preferably enriched in tumor tissues and actively interacted with cholangiocytes.LGALS1 was verified as a marker gene of Fibroblast_LUM+,contributing to the malignant phenotype of ICC.Higher amount of LGALS1+fibroblasts was associated with poorer overall survival of ICC patients.Mechanistically,LGALS1+fibroblasts activated the proliferation and migration of tumor cells by upregulating the expression levels of CCR2,ADAM15,andβ-integrin.Silencing LGALS1 in cancer-associated fibroblasts(CAFs)suppressed CAF-augmented tumor cell migration and invasion in vitro as well as tumor formation in vivo,suggesting that blockade of LGALS1 serves as a potential therapeutic approach for ICC.Taken together,our single-cell analysis provides insight into the interaction between malignant cells and specific subtypes of fibroblasts,which contributes to better understanding of the intratumor heterogeneity in ICC and the development of novel strategies for the treatment of ICC by targeting fibroblasts in the tumor microenvironment.

关 键 词：single-cell RNA sequencing(scRNA-seq) intrahepatic cholangiocarcinoma(ICC) LGALS1 FIBROBLAST 

分 类 号：R735.8[医药卫生—肿瘤]