Abstract A major problem in the treatment of ovarian cancer is the heterogeneity among ovarian tumors. DNA and RNA sequencing studies have demonstrated both intertumoral and intratumoral genetic variation. Despite efforts to elucidate common signaling pathways among various ovarian cancer subtypes, few have led to meaningful patient stratification or individualized targeted molecular therapies. A theoretical new approach to the treatment of ovarian cancer would be to target the signaling pathways that are essential to the development of the HGSOC progenitor cells, the secretory epithelium of the fallopian tube (FT). PAX8, a transcription factor that identifies and sustains high-grade serous ovarian carcinomas (HGSOC), is also the main regulator of FT development. We investigated whether blocking the ability of PAX8 to influence its gene targets, either by interrupting PAX8 protein-protein interactions or by inhibiting the products of PAX8-driven signaling, has the potential to eliminate the primary growth stimulus for high-grade serous tumors. Herein, we have identified SOX17 as a bona fide PAX8-interacting partner and elucidated their collaborative impact on HGSOC. We observed that PAX8 and SOX17 are master regulators of HGSOC identity, as both were found binding in super-enhancer regions regulating most of the same set of genes. Ontology analysis after PAX8 or SOX17 loss showed alteration in three main pathways: cell cycle, apoptosis, and angiogenesis. Most remarkably, we discovered that PAX8 and SOX17 regulate angiogenesis in vitro and in vivo by suppressing SERPINE1, which enables VEGFR2 signaling pathway. These results broaden our understanding of the roles of PAX8 and SOX17 in the regulation of angiogenesis and suggest novel therapeutic strategies that could overcome ovarian cancer heterogeneity and resistance. Citation Format: Daniele Chaves-Moreira, Marilyn A. Mitchell, Jessica Rendi, Robbin Nameki, Donita C. Brady, Simone Sidoli, Benjamin Garcia, Patrice J. Morin, Kate Lawrenson, Ronny Drapkin. PAX8 drives ovarian cancer angiogenesis through interaction with SOX17 [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 A37.