Overcoming platinum-resistant ovarian cancer targeting the activated JAK-STAT pathways via extracellular vesicles.

Platinum-resistant ovarian cancer (PROC) is a clinically severe unresolved issue, and it remains unclearly defined by molecular biology. Extracellular vesicles (EVs) play an essential role in cell-to-cell communication in the tumor microenvironment. This study aimed to investigate the molecular mechanisms of PROC, focusing on the unique ascites environment of ovarian cancer. Multi-transcriptome analyses using clinical samples revealed that PROC exhibited an activated Janus kinase (JAK)/signal transducer and activator of transcription pathway with high JAK1 expression in cancer cells. Immunohistochemistry for patient tissues confirmed the negative association between JAK1 expression and platinum response. JAK inhibitors were effective in PROC cell lines and cell- and patient-derived xenograft models, as well as synergistic with platinum. Furthermore, small RNA sequencing indicated that activated peritoneal mesothelial cell-derived EVs enriched in miR135a-5p increased JAK expression and platinum resistance in cancer cells. Collectively, EVs in ascites regulated platinum sensitivity in ovarian cancer cells, and JAK targeting therapeutic strategy overcomes PROC.