Abstract B71: Investigating the role of PAX8 in modulating the tumor microenvironment of high-grade serous ovarian cancer

Abstract

Abstract High-grade serous ovarian cancer (HGSOC), the most common and lethal form of ovarian cancer, is a highly heterogeneous disease. HGSOC is rarely detected early, and likely arises from the fimbriated end of the fallopian tube epithelium (FTE), and in some cases, the ovarian surface epithelium (OSE). PAX8 is a commonly used biomarker for ovarian serous tumors and is expressed in 80-96% of HGSOC. Although the OSE does not express PAX8, murine models of HGSOC derived from the OSE acquire PAX8, suggesting that it is not only a marker of Müllerian origin, but also an essential part of HGSOC progression, potentially from both the OSE and FTE. Previously, we showed that PAX8 deletion by CRISPR and shRNA in HGSOC cell lines caused apoptosis and reduced cell migration and invasion. We performed secretome analysis of PAX8 deleted cells and found a reduction of the extracellular matrix (ECM) component fibronectin. This finding was validated by immunoblotting and immunofluorescence in PAX8 deleted HGSOC cells. We have generated several murine FTE-derived tumor models (PTEN/KRAS/p53 alterations) and knocked down PAX8 in these models. These syngeneic fallopian tube-derived tumor models will be allografted into immune intact FVB mice and the tumors will be used to determine if PAX8 loss impacts immune cell infiltration via changes in ECM. Additionally, we are using a novel high-throughput screening (HTS) assay to identify small molecules that can function to inhibit PAX8 promoter activation and lead to reduced PAX8 expression. We have generated a stable cell line using murine FTE cells expressing the PAX8 promoter-luciferase reporter, which will be used to screen a library of FDA-approved drugs (Prestwick Library, ca. 1,200 members). Overall, this study would help us to validate PAX8 as a regulator of ECM deposition in the tumor microenvironment and identify an effective drug for treatment of ovarian cancers derived from both the FTE and OSE. Citation Format: Amrita Salvi, Laura Hardy, Samantha Watry, Melissa Pergande, Stephanie M. Cologna, Joanna E. Burdette. Investigating the role of PAX8 in modulating the tumor microenvironment of high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B71.