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Ovarian cancer (OC) is characterized by frequent widespread peritoneal metastasis. Cancer‐associated fibroblasts (CAFs) represent a critical stromal component of metastatic niche and promote omentum metastasis in OC patients. However, the role of exosomes derived from omental CAFs in metastasis remains unclear. We isolated exosomes from primary omental normal fibroblasts (NFs) and CAFs from OC patients (NF‐Exo and CAF‐Exo, respectively) and assessed their effect on metastasis. In mice bearing orthotopic OC xenografts, CAF‐Exo treatment led to more rapid intraperitoneal tumor dissemination and shorter animal survival. Similar results were observed in mice undergoing intraperitoneal injection of tumor cells. Among the miRNAs downregulated in CAF‐Exo, miR‐29c‐3p in OC tissues was associated with metastasis and survival in patients. Moreover, increasing miR‐29c‐3p in CAF‐Exo significantly weakened the metastasis‐promoting effect of CAF‐Exo. Based on RNA sequencing, expression assays, and luciferase assays, matrix metalloproteinase 2 (MMP2) was identified as a direct target of miR‐29c‐3p. These results verify the significant contribution of exosomes from omental CAFs to OC peritoneal metastasis, which could be partially due to the relief of MMP2 expression inhibition mediated by low exosomal miR‐29c‐3p.

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