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

TL;DR

This study identifies FRY as a key protein that helps ovarian cancer spread, linking immune signals to tumor invasion through the PI3K/AKT pathway.

Contribution

The novel finding is that FRY, a microtubule-binding protein, mediates macrophage-driven ovarian cancer invasion via the PI3K/AKT pathway.

Findings

FRY expression in ovarian cancer cells is induced by macrophage-derived conditioned medium.

FRY knockdown reduces invasion without affecting cell viability, indicating a role in motility.

FRY is a downstream effector of PI3K/AKT signaling and is regulated by the transcription factor NFIX.

Abstract

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.

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