Reciprocal tumor-platelet interaction through the EPHB1-EFNB1 axis in the liver metastatic niche promotes metastatic tumor outgrowth in pancreatic ductal adenocarcinoma  

作　　者：Lin-Li Yao Wei-Ting Qin Li-Peng Hu Tie-Zhu Shi Jian Yu Yang Qing Li Hui-Zhen Nie Jun Li Xu Wang Lei Zhu De-Jun Liu Yan-Li Zhang Shu-Heng Jiang Zhi-Gang Zhang Xiao-Mei Yang Dong-Xue Li Xue-Li Zhang 

机构地区：[1]State Key Laboratory of Systems Medicine for Cancer,Shanghai Cancer Institute,Ren Ji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,P.R.China [2]Department of Radiation Oncology,Ren Ji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,P.R.China [3]Department of Urology,Shanghai General Hospital,Shanghai Jiao Tong University,Shanghai,P.R.China [4]Department of Biliary-Pancreatic Surgery,Ren Ji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,P.R.China

出　　处：《Cancer Communications》2025年第2期143-166,共24页癌症通讯(英文)

基　　金：Natural Science Foundation of Shanghai,Grant/Award Number:22ZR1460000;Shanghai Municipal Health Commission,Grant/Award Number:202340202;National Natural Science Foundation of China,Grant/Award Numbers:82073023,82103357,82173153,82230087,82273228,82303278,82350123,82372821,92168111;Innovative research team of high-level local universities in Shanghai,Grant/Award Number:SHSMU-ZDCX20210802。

摘　　要：Background:The interaction between the metastatic microenvironment and tumor cells plays an important role in metastatic tumor formation.Platelets play pivotal roles in hematogenous cancer metastasis through tumor cell-platelet interaction in blood vessels.Pancreatic ductal adenocarcinoma(PDAC)is a highly lethal malignancy distinguished by its notable tendency to metastasize to the liver.However,the role of platelet in the liver metastatic niche of PDAC remains elusive.This study aimed to elucidate the role of platelets and their interactions with tumor cells in the liver metastatic niche of PDAC.Methods:An mCherry niche-labeling system was established to identify cells in the liver metastatic niche of PDAC.Platelet depletion in a liver metastasis mouse model was used to observe the function of platelets in PDAC liver metastasis.Gain-of-function and loss-of-function of erythropoietin-producing hepatocellular receptor B1(Ephb1),tumor cell-platelet adhesion,recombinant protein,and tryptophan hydroxylase 1(Tph1)-knockout mice were used to study the crosstalk between platelets and tumor cells in the liver metastatic niche.Results:The mCherry metastatic niche-labeling system revealed the presence of activated platelets in the liver metastatic niche of PDAC patients.Platelet depletion decreased liver metastatic tumor growth in mice.Mechanistically,tumor cell-expressed EPHB1 and platelet-expressed Ephrin B1(EFNB1)mediated contact-dependent activation of platelets via reverse signaling-mediated AKT signaling activation,and in turn,activated platelet-released 5-HT,further enhancing tumor growth.Conclusion:We revealed the crosstalk between platelets and tumor cells in the liver metastatic niche of PDAC.Reciprocal tumor-platelet interaction mediated by the EPHB1-EFNB1 reverse signaling promoted metastatic PDAC outgrowth via 5-HT in the liver.Interfering the tumor-platelet interaction by targeting the EPHB1-EFNB1 axis may represent a promising therapeutic intervention for PDAC liver metastasis.

关 键 词：Liver metastatic niche Tumor-platelet interaction Axon guidance molecule Reverse signaling 5-HT 

分 类 号：R73[医药卫生—肿瘤]