Journal Article

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

Mak, Celia S. L., Sharma, Rakesh, Wang, Xueyu, Siu, Michelle K. Y., Mo, Yulan, Tang, Hermit W. M., Leung, Leanne L., Ngan, Hextan Y. S., Hui, Lynn M. N., Chan, Wai-Sun, Xu, Dakang, Chan, David W., Yung, Mingo M. H., Chan, Karen K. L., Tsui, Stephen K. W.

2023

Overview

Background Metastatic 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. Methods PCR-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. Results Hsa-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. Conclusions This 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.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Adaptor Proteins, Signal Transducing - genetics / Analysis / Animals / Biological products / Biomedical and Life Sciences / Biomedicine / Cancer Research / cancer-associated fibroblasts / Chromatography, Liquid / Cytokines / Development and progression / Female / Genetic engineering / Hippo/YAP1/pathway / Humans / Luciferase / Metastasis / Mice / MicroRNA / MicroRNAs - genetics / miR-141 / Oncology / Ovarian cancer / Ovarian Neoplasms - genetics / Peritoneal metastases / Proteomics / Tandem Mass Spectrometry / Tumor Microenvironment / Tumor-stroma interactions