Yao Lin-Li, Qin Wei-Ting, Hu Li-Peng, Shi Tie-Zhu, Yu Yang Jian, Li Qing, Nie Hui-Zhen, Li Jun, Wang Xu, Zhu Lei, Liu De-Jun, Zhang Yan-Li, Jiang Shu-Heng, Zhang Zhi-Gang, Yang Xiao-Mei, Li Dong-Xue, Zhang Xue-Li
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.
Department of Radiation Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P. R. China.
Cancer Commun (Lond). 2025 Feb;45(2):143-166. doi: 10.1002/cac2.12637. Epub 2024 Dec 8.
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.
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.
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.
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.
转移微环境与肿瘤细胞之间的相互作用在转移性肿瘤形成中起重要作用。血小板通过血管中的肿瘤细胞 - 血小板相互作用在血行性癌症转移中发挥关键作用。胰腺导管腺癌（PDAC）是一种高度致命的恶性肿瘤，其显著特点是易于转移至肝脏。然而，血小板在PDAC肝转移微环境中的作用仍不清楚。本研究旨在阐明血小板及其与肿瘤细胞在PDAC肝转移微环境中的相互作用。
建立mCherry微环境标记系统以识别PDAC肝转移微环境中的细胞。利用肝转移小鼠模型中的血小板耗竭来观察血小板在PDAC肝转移中的功能。通过促红细胞生成素产生肝细胞受体B1（Ephb1）的功能获得和功能丧失、肿瘤细胞 - 血小板粘附、重组蛋白以及色氨酸羟化酶1（Tph1）基因敲除小鼠来研究肝转移微环境中血小板与肿瘤细胞之间的串扰。
mCherry转移微环境标记系统揭示了PDAC患者肝转移微环境中存在活化的血小板。血小板耗竭减少了小鼠肝转移肿瘤的生长。机制上，肿瘤细胞表达的EPHB1和血小板表达的Ephrin B1（EFNB1）通过反向信号介导的AKT信号激活介导血小板的接触依赖性激活，进而，活化的血小板释放5 - 羟色胺（5 - HT），进一步促进肿瘤生长。
我们揭示了PDAC肝转移微环境中血小板与肿瘤细胞之间的串扰。由EPHB1 - EFNB1反向信号介导的肿瘤 - 血小板相互作用通过肝脏中的5 - HT促进转移性PDAC的生长。通过靶向EPHB1 - EFNB1轴干扰肿瘤 - 血小板相互作用可能是PDAC肝转移的一种有前景的治疗干预措施。
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