Tumor-secreted exosomal miR-141 activates tumor-stroma interactions and controls premetastatic niche formation in ovarian cancer metastasis

Molecular Cancer

Research

Rakesh Sharma¹  Leanne L. Leung²  Wai-Sun Chan²  Hermit W. M. Tang²  Xueyu Wang²  Michelle K. Y. Siu²  Yulan Mo²  Karen K. L. Chan²  Hextan Y. S. Ngan²  Celia S. L. Mak²  Lynn M. N. Hui²  Mingo M. H. Yung²  David W. Chan³  Dakang Xu⁴  Stephen K. W. Tsui⁵ 

[1] Centre for PanorOmic Sciences Proteomics and Metabolomics Core, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China;Department of Obstetrics & Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China;Department of Obstetrics & Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China;School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China;School of Medicine, The Chinese University of Hong Kong-Shenzhen, 518172, Shenzhen, China;Faculty of Medical Laboratory Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200030, Shanghai, China;School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China;

关键词: miR-141;    Hippo/YAP1/pathway;    Ovarian cancer;    Tumor-stroma interactions;    Peritoneal metastases;    cancer-associated fibroblasts;   

DOI  :  10.1186/s12943-022-01703-9

 received in 2022-09-14, accepted in 2022-12-19,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundMetastatic colonization is one of the critical steps in tumor metastasis. A pre-metastatic niche is required for metastatic colonization and is determined by tumor-stroma interactions, yet the mechanistic underpinnings remain incompletely understood.MethodsPCR-based miRNome profiling, qPCR, immunofluorescent analyses evaluated the expression of exosomal miR-141 and cell-to-cell communication. LC-MS/MS proteomic profiling and Dual-Luciferase analyses identified YAP1 as the direct target of miR-141. Human cytokine profiling, ChIP, luciferase reporter assays, and subcellular fractionation analyses confirmed YAP1 in modulating GROα production. A series of in vitro tumorigenic assays, an ex vivo model and Yap1 stromal conditional knockout (cKO) mouse model demonstrated the roles of miR-141/YAP1/GROα/CXCR1/2 signaling cascade. RNAi, CRISPR/Cas9 and CRISPRi systems were used for gene silencing. Blood sera, OvCa tumor tissue samples, and tissue array were included for clinical correlations.ResultsHsa-miR-141-3p (miR-141), an exosomal miRNA, is highly secreted by ovarian cancer cells and reprograms stromal fibroblasts into proinflammatory cancer-associated fibroblasts (CAFs), facilitating metastatic colonization. A mechanistic study showed that miR-141 targeted YAP1, a critical effector of the Hippo pathway, reducing the nuclear YAP1/TAZ ratio and enhancing GROα production from stromal fibroblasts. Stromal-specific knockout (cKO) of Yap1 in murine models shaped the GROα-enriched microenvironment, facilitating in vivo tumor colonization, but this effect was reversed after Cxcr1/2 depletion in OvCa cells. The YAP1/GROα correlation was demonstrated in clinical samples, highlighting the clinical relevance of this research and providing a potential therapeutic intervention for impeding premetastatic niche formation and metastatic progression of ovarian cancers.ConclusionsThis study uncovers miR-141 as an OvCa-derived exosomal microRNA mediating the tumor-stroma interactions and the formation of tumor-promoting stromal niche through activating YAP1/GROα/CXCRs signaling cascade, providing new insight into therapy for OvCa patients with peritoneal metastases.

【 授权许可】

CC BY   
© The Author(s) 2023

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