Abstract 2209: RelB drives integrin-mediated stress tolerance and relapse in high-grade serous ovarian cancer.

Abstract High-grade serous ovarian cancer (HGSOC) initially responds to chemotherapy but frequently relapses with chemoresistant disease, potentially driven by cancer stem-like cells (CSCs), a minority tumor cell population with enhanced chemoresistance and tumor-initiation capacity that persists following treatment. We previously demonstrated that NF-κB signaling is upregulated in HGSOC and promotes stemness features in ovarian cancer cells including drug resistance, asymmetric division, tumor-initiation capacity, and epithelial to mesenchymal transition (EMT). Here, we investigated potential mechanisms by which this signaling cascade supports stress tolerance and tumor regrowth following chemotherapy to identify new therapeutic targets to prevent relapse. We found that NF-κB transcription factors RelA and RelB commonly regulate extracellular matrix organization genes but differentially regulate specific integrin subunits, including ITGAV (αV) by RelA and ITGB3 (β3) by RelB. Given the clinical feasibility of targeting integrins we investigated αVβ3 in ovarian CSCs. We show that αVβ3+ cells have significantly enhanced tumor-initiation capacity relative to αVβ3- cells and αVβ3 and αVβ5 are enriched on ovarian CSCs following standard of care chemotherapy. We developed a relapse model that demonstrates αVβ3 expression on ∼90% of cells derived from re-established tumors and αVβ3+ cells exhibit preferential growth on mesentery, which is mediated by RelB. Importantly, knockdown of RelB combined with inhibition of αVβ3 and αVβ5 eradicated stress-tolerant cells, reduced overall tumor burden, and significantly prolonged survival following chemotherapy. Studies are underway to elucidate stromal responses to cytotoxic chemotherapy in peritoneal tissues that generate a modulated matrisome characterized by increased vitronectin and fibronectin. These tissues, which include the mesentery, may be susceptible to colonization of stress tolerant cells expressing αVβ3 and αVβ5 following chemotherapy and thus may play a significant role in relapse. Crucially, this work proposes integrins as promising therapeutic targets for HGSOC and indicates distinct roles for NF-kB transcription factors in regulating integrin expression and metastatic growth in this disease. Citation Format: Omar Lujano Olazaba, Mikella Robinson, Greg J. Jordan, Sofia Howe, Cassidy Lucht, Anna Platen, Dishant Vandra, Mena Shammas, Katelyn Shelby, Ingrid Niesman, Christina M. Annunziata, Carrie Danielle House. RelB drives integrin-mediated stress tolerance and relapse in high-grade serous ovarian cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2209.