Alternative NF-κB Signaling Promotes αVβ3-Mediated Stress Tolerance and Relapse in High-Grade Serous Ovarian Cancer

Committee Members

• Dr. Carrie D. House (Chair), SDSU
• Dr. Angelica Riestra, SDSU
• Dr. Parag Katira, SDSU
• Dr. David Schlaepfer, UCSD
• Dr. Karl Willert, UCSD

Abstract

High-grade serous ovarian cancer  initially responds to chemotherapy but frequently relapses with chemoresistant disease, potentially driven by cancer stem-like cells (CSCs) that share many attributes with conventional stem cells.

TWEAK–Fn14–NF-κB signaling regulates integrin αVβ3 expression on CD117⁺ ovarian CSCs, with RelA promoting ITGAV and RelB promoting ITGB3 expression, indicating roles for classical and alternative NF-κB signaling. Given αVβ3’s role in stress responses, chemotherapy resistance, and matrix adhesion, we investigated its involvement in CSC survival and tumor repopulation within chemotherapy-altered stroma.

Our in vitro and in vivo data show chemotherapy increases fibroblast vitronectin and fibronectin production and promotes TWEAK–Fn14–NF-κB–mediated αVβ3 expression, supporting stress-tolerant CSC survival. αVβ3⁺ cells exhibit greater metastatic ability in chemotherapy-altered tissues, and relapse models show enrichment of αVβ3⁺ cells and mesenteric growth mediated by RelB.

Inhibition of RelB, αVβ3, and αVβ5 during chemotherapy administration eradicates αVβ3⁺ stress tolerant cells, inhibits omental burden, and significantly prolongs survival, highlighting new potential therapeutic targets for ovarian cancer.