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

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Ovarian cancer is a deadly gynecological malignancy characterized by early spread and peritoneal metastasis.
• Tumor-associated macrophages within the tumor microenvironment (TME) promote cancer cell invasion, but molecular links are unclear.

Purpose of the Study:

• To identify molecular mediators of macrophage-driven invasion in ovarian cancer.
• To investigate the role of FRY, a microtubule-binding protein, in ovarian cancer progression.

Main Methods:

• Used conditioned medium from ovarian cancer-stimulated macrophages (OCM) to induce FRY expression in ovarian cancer cells.
• Performed FRY knockdown experiments to assess its functional role in invasion.
• Investigated FRY's mechanistic role in epithelial-mesenchymal transition (EMT) and PI3K/AKT signaling.
• Identified NFIX as a regulator of FRY and CXCR1/2 axis inhibition with reparixin.

Main Results:

• Elevated FRY levels correlate with advanced ovarian cancer stage and reduced patient survival.
• FRY knockdown abrogated OCM-induced invasion, confirming its specific role in cell motility.
• FRY facilitates EMT and is essential for AKT1-driven invasion.
• Macrophage signaling upregulates NFIX, which drives FRY transcription, and reparixin blocks this pathway.

Conclusions:

• FRY is a critical, macrophage-induced mediator of ovarian cancer cell invasion.
• FRY's role in facilitating EMT and linking macrophage signaling to PI3K/AKT activation highlights its significance.
• Targeting the FRY-NFIX axis or CXCR1/2 signaling presents a potential therapeutic strategy for ovarian cancer.