Ovarian Cancer (OvCa) is a disease that affects postmenopausal women, with high-grade serous ovarian carcinoma being the most common and lethal histopathological type. High-grade serous carcinoma develops from malignant cells that originate from tubal epithelium. Many patients are asymptomatic in the early stages of OvCa, thus going undetected, leading to higher patient mortality rates. Currently, 51% of women are not diagnosed until Stage III and 29% are diagnosed during Stage IV. One of the major limitations in current research is the lack of understanding of key drivers of clinical phenotypes and determination diagnostic biomarkers to provide targeted therapeutic approaches. Immunotherapy has emerged as a major treatment modality for cancer. Chemokines and their receptors play a significant role in immune cell chemotaxis that drives inflammation and immunity. Our laboratory was the first to show that CXCL13-CXCR5 signaling mediates prostate, breast and lung cancer cell growth, migration, invasion, and survival. Furthermore, we provided evidence that CXCL13 and CXCR5 are highly elevated in OvCa cell lines and clinical samples. These previous findings provided the rationale to support the hypothesis CXCL13-CXCR5 signaling promotes OvCa progression, metastasis and survival. In this study we further analyzed transcriptome data to determine possible molecular mechanisms and CXCL13-CXCR5 signaling pathways controlling OvCa progression. Weighted Gene Network Co-expression (WGCNA) analysis was used to identify gene co-expression networks correlated with aggressive OvCa clinical phenotypes. Using Ingenuity Pathway Analysis (IPA), we identified several CXCL13-CXCR5 associated hub genes that reveal gene-gene interactions, upstream regulators and biological pathways that drive OvCa progression. Of interest, WGCNA-designated Blue module contained CXCR5 along with various co-expressed genes, including RB1, PIK3 C3, GNAI1 that are known to facilitate the progression of OvCa as well as LTB and TNFRSF11B, which have been shown to mediate tertiary lymphoid structure formation. Furthermore, the Blue module genes were significantly (p = 0.04) associated with age at diagnosis. The Salmon module, closely related to the Blue module and, significantly (p = 0.01) correlated with relapse. Importantly, the Salmon module co-Expressed genes, included AURKB and CDCA8 and cell cycle checkpoint regulatory genes, which have shown to be prominent in OvCa recurrence. Taken together, our study suggest an important role of CXCL13-CXCR5 signaling and reveals an important set of co-expressed epigengenes involved in OvCa relapse.
Citation Format: Kaylin Carey, Tiara Griffen, Corey Young, Courtney Dill, James Lillard. A multi-variate transcriptome analysis of CXCR5-CXCL13 signaling in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1971.