miRNAs derived from plasma small extracellular vesicles predict organo-tropic metastasis of gastric cancer

Peritoneum, liver and lymph node are the most common metastatic sites of gastric cancer (GC). Biomarkers for GC's organo-tropic metastasis remained largely unknown, which was investigated in this study from the perspective of small extracellular vesicle (sEV)-derived miRNAs.Plasma from treatment-naïve GC patients including no metastasis (M0), peritoneal metastasis (PM), hepatic metastasis (HM) and distant lymph node metastasis (dLNM)) were divided into one discovery (N = 40), one training (N = 40) and one validating cohort (N = 86), then assessed by sEV-miRNA-sequencing and sEV-miRNA-qPCR. Functional explorations were also performed for verification.The expression profiles of sEV-miRNAs varied greatly across different metastatic patterns. Based on logistic regression models, we constructed signatures for M0 (hsa-miR-186-5p/hsa-miR-200c-3p/hsa-miR-429/hsa-miR-5187-5p/hsa-miR-548ae-5p), PM (hsa-miR-200c-3p/hsa-miR-429), HM (hsa-miR-200c-3p/hsa-miR-429) and dLNM (hsa-miR-324-5p/hsa-miR-374a-5p/hsa-miR-429/hsa-miR-548ae-5p). These signatures vigorously characterized organo-tropic metastasis (all displaying AUC > 0.8, consistency ≥ 75%), and effectively conjectured the risk of future metastasis within 5 years (accuracy 45.5% for occurrence, 70% for organotropism, P = 0.002 for prognostic diversity). Additionally, we explored these seven biomarker miRNAs' impact on GC's in vitro motility and discussed their potential involvement in cancer-related biological processes and pathways.Our work highlighted that plasma sEV-miRNAs powerfully characterized and predicted the organo-tropic metastasis of GC and provided new insight into the applications of sEV-based liquid biopsy in clinical practice.