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

IF 20.1 1区 医学 Q1 ONCOLOGY
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
{"title":"Reciprocal tumor-platelet interaction through the EPHB1-EFNB1 axis in the liver metastatic niche promotes metastatic tumor outgrowth in pancreatic ductal adenocarcinoma","authors":"Lin-Li Yao,&nbsp;Wei-Ting Qin,&nbsp;Li-Peng Hu,&nbsp;Tie-Zhu Shi,&nbsp;Jian Yu Yang,&nbsp;Qing Li,&nbsp;Hui-Zhen Nie,&nbsp;Jun Li,&nbsp;Xu Wang,&nbsp;Lei Zhu,&nbsp;De-Jun Liu,&nbsp;Yan-Li Zhang,&nbsp;Shu-Heng Jiang,&nbsp;Zhi-Gang Zhang,&nbsp;Xiao-Mei Yang,&nbsp;Dong-Xue Li,&nbsp;Xue-Li Zhang","doi":"10.1002/cac2.12637","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>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 (<i>Ephb1</i>), tumor cell-platelet adhesion, recombinant protein, and tryptophan hydroxylase 1 (<i>Tph1</i>)-knockout mice were used to study the crosstalk between platelets and tumor cells in the liver metastatic niche.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>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.</p>\n </section>\n </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 2","pages":"143-166"},"PeriodicalIF":20.1000,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12637","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Communications","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cac2.12637","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

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.

Abstract Image

肝转移生态位中通过EPHB1-EFNB1轴的肿瘤-血小板相互作用促进胰腺导管腺癌转移性肿瘤的生长。
背景:转移性微环境与肿瘤细胞的相互作用在转移性肿瘤的形成中起着重要作用。血小板通过血管中肿瘤细胞与血小板的相互作用在血行性肿瘤转移中起关键作用。胰腺导管腺癌(PDAC)是一种高度致死性的恶性肿瘤,其显著的特点是易于转移到肝脏。然而,血小板在PDAC肝转移生态位中的作用仍然难以捉摸。本研究旨在阐明血小板在PDAC肝转移生态位中的作用及其与肿瘤细胞的相互作用。方法:建立mCherry小生境标记系统,鉴定PDAC肝转移小生境细胞。采用小鼠肝转移模型,观察血小板在PDAC肝转移中的作用。利用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、重组蛋白和色氨酸羟化酶1 (Tph1)敲除小鼠,研究了肝转移生态位中血小板与肿瘤细胞之间的串扰。结果:mCherry转移小生境标记系统显示PDAC患者肝转移小生境中存在活化血小板。血小板消耗降低小鼠肝转移瘤生长。在机制上,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接触依赖性活化,进而激活血小板释放的5-HT,进一步促进肿瘤生长。结论:我们揭示了PDAC肝转移生态位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5-HT在肝脏中促进转移性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一种有希望的PDAC肝转移治疗干预措施。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信