RelB drives integrin-mediated stress tolerance and relapse in high-grade serous ovarian cancer

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 (alphaV) by RelA and ITGB3 (beta3) by RelB. Given the clinical feasibility of targeting integrins we investigated alphaVbeta3 in ovarian CSCs. We show that alphaVbeta3 + cells have significantly enhanced tumor-initiation capacity relative to alphaVbeta3 - cells and alphaVbeta3 and alphaVbeta5 are enriched on ovarian CSCs following standard of care chemotherapy. We developed a relapse model that demonstrates alphaVbeta3 expression on ~90% of cells derived from re-established tumors and alphaVbeta3 + cells exhibit preferential growth on mesentery, which is mediated by RelB. Importantly, knockdown of RelB combined with inhibition of alphaVbeta3 and alphaVbeta5 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 alphaVbeta3 and alphaVbeta5 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.