FRY Mediates THP1-Driven Ovarian Cancer Invasion Through the PI3K/AKT Pathway

Ovarian cancer remains the most lethal gynecological malignancy, largely due to its early dissemination and extensive peritoneal metastasis. The tumor microenvironment (TME), particularly tumor-associated macrophages, promotes this invasive phenotype; however, the precise molecular effectors linking immune-to-tumor signaling remain unclear. We identified FRY, a microtubule-binding protein previously uncharacterized in ovarian pathology, as a critical mediator of macrophage-driven invasion. We observed that conditioned medium from ovarian cancer-stimulated macrophages (OCM) robustly induced FRY expression in ovarian cancer cells. Clinically, elevated FRY levels correlate with advanced tumor stage and poor patient survival. Functionally, FRY knockdown significantly abrogated OCM-induced invasion without affecting cell viability, highlighting its specific role in motility. Mechanistically, FRY facilitates epithelial-mesenchymal transition (EMT) and acts as an essential downstream effector of the PI3K/AKT signaling cascade; notably, FRY was required for AKT1-driven invasive behaviors. Furthermore, we identified the transcription factor NFIX as a key regulator of FRY expression. Macrophage-derived signals upregulate NFIX, which directly regulates FRY transcription. Pharmacological inhibition of the CXCR1/2 axis with reparixin effectively blocked OCM-mediated induction of both NFIX and FRY, suggesting that chemokine signaling initiates this pro-invasive loop. Collectively, these findings suggest that FRY is a macrophage-driven mediator of invasion and underscore its potential relevance in ovarian cancer.