Description
Ovarian cancer causes more deaths each year than any other cancer of the female reproductive system. While there is an initial high response rate to cytotoxic chemotherapy, over 80% of women diagnosed with advanced disease relapse within 24 months, presenting an urgent need to better understand the mechanisms contributing to relapse. Our lab previously established an essential role of noncanonical NF-κB signaling in maintaining chemoresistant, stem-like tumor-initiating cells (TICs) in ovarian cancer. Our lab also discovered that the multifunctional cytokine, TNF-like weak inducer of apoptosis (TWEAK), supports stemness features in ovarian TICs via noncanonical NF-κB pathway activation. However, the distinct cellular source of soluble TWEAK in the ovarian tumor microenvironment (TME) is not fully understood. Studies indicate that different stromal cells, primarily macrophages, secrete soluble TWEAK in the TME and this may be enhanced following chemotherapy. We previously found high levels of TWEAK in the human ovarian TME, which also shows an abundance of macrophages. Thus, we hypothesized that macrophages in the ovarian TME are secreting TWEAK to induce alternative NF-κB activation in ovarian TICs, thereby supporting drug resistance and cancer recurrence. Using the THP-1 monocytic cell line, we will investigate the roles of the pro-inflammatory M1 and immune-suppressive M2 macrophage phenotypes and their persistence following chemotherapy, role in TWEAK secretion, and activation of ovarian cancer cells. We found M1-like macrophages were enriched across all macrophage populations after carboplatin treatment, suggesting chemotherapy enriches for the M1 phenotype. We further found M1-like macrophages consistently had higher expression of TWEAK. A deeper understanding of the mechanisms supporting relapse will enable the development of novel therapeutic approaches to prevent disease progression and recurrence.
