Role of exosomal miR-141 in pro-metastatic tumor-stroma interactions in ovarian cancer

Abstract

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. Previously, we showed that hsa-miR-141-3p (miR-141) is generally elevated and enhances anoikis resistance via targeting the KLF12/Sp1/survivin signaling cascade, facilitating metastatic cancer progression in ovarian cancer. Here, we report that 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), thereby facilitating metastatic colonization. A mechanistic study showed that miR-141 targeted Yes-associated protein (YAP1), a key effector of the Hippo pathway, promoting Tafazzin (TAZ), reducing nuclear YAP1/TAZ ratio and enhancing Tafazzin (TAZ)- and TEAD1-mediated transcriptional activation of the oncogenic factors GROα and EMMPRIN in stromal fibroblasts. Genetic inhibition of YAP1 induced a direct increase in transcription of GROα and EMMPRIN, in turn, forming an ideal pre-metastatic niche in tumor microenvironment (TME) under conditions of chronic inflammation favoring metastatic colonization and progression. Conversely, enforced expression of YAP1 markedly reduced the levels of GROα and EMMPRIN. Stromal-specific knockout (cKO) of Yap1 in a murine model shaped a GROα-enriched microenvironment and promoted tumor colonization in vivo, but this effect was reversed after Cxcr1/2 depletion in ovarian cancer 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.