Impact of senescent fibroblasts secretome in ovarian cancer dissemination

Aging is a significant risk factor in ovarian cancers, which remains one of the most lethal gynecological malignancies. Over 50 % of ovarian cancer cases occur in women aged 65 and older. During aging, senescent cells progressively accumulate in various tissues, contributing to structural and inflammatory changes in the tumor microenvironment. While recent studies have underscored the role of the senescent mesothelial cells in facilitating cancer cell dissemination, the contribution of senescent fibroblasts that are a major component of the connective tissue, remains elusive. In this study, we first characterized the senescent phenotype of human ovarian fibroblasts, with a focus on extracellular matrix (ECM) remodeling and the senescence-associated secretory phenotype (SASP). Senescent ovarian fibroblasts exhibited an accumulation of intracellular Fibronectin (Fn), impaired fibrillar Fn into ECM assembly, and marked alterations in ECM organization. SASP profiling revealed a pro-inflammatory secretome enriched in immune-modulatory cytokines and factors potentially involved in cancer cell dissemination and metastasis. We then evaluated the influence of the senescent fibroblast secretome on ovarian cancer cell behavior. While it did not alter cancer cell proliferation, it conferred resistance to apoptosis and significantly enhanced cancer cell migration and invasion. Altogether, our findings highlight the role of senescent ovarian fibroblasts in promoting cancer cell dissemination and suggest that age-related stromal changes contribute to disease progression.