CAF-derived exosomal circMPP6 drives ovarian cancer metastasis by coordinating nuclear and cytoplasmic regulation of ADAM22 to activate TGF-β/Smad signaling

Cancer-associated fibroblasts (CAFs) contribute to the metastatic progression of high-grade serous ovarian cancer (HGSOC), partly through the transfer of regulatory RNAs via exosomes.Here, we identify a circRNA, circMPP6 as a key pro-metastatic factor enriched in CAF-derived exosomes.circMPP6 is upregulated in metastatic HGSOC tissues and is associated with poor prognosis.In HGSOC cells, nuclear circMPP6 interacts with SFPQ and NONO to stabilize ADAM22 mRNA, whereas cytoplasmic circMPP6 binds EEF1A2 to enhance ADAM22 protein expression.Elevated ADAM22 levels activate TGF-/Smad2/3 signaling via binding to ITGB1, promoting proliferation, migration, and invasion in vitro and metastasis in vivo.Silencing circMPP6 or disrupting the ADAM22 axis attenuates these oncogenic phenotypes.In CAFs, its loading into exosomes is mediated by hnRNPA2B1, enabling its transfer to adjacent tumor cells.These findings reveal a dual regulatory mechanism by which CAFs-derived exosomal circMPP6 enhances ADAM22 expression and activates pro-metastatic TGF- signaling in HGSOC.Our study highlights circMPP6 as a potential therapeutic target and critical mediator of stromal-tumor communication in ovarian cancer metastasis.