Integrative multi-omic analysis reveals a PAX8-driven gene network linking tumor stemness to therapy response in ovarian cancer.

Abstract

The transcription factor PAX8 is expressed in most ovarian tumors, being associated with increased tumorigenesis. Although recent studies have addressed the gene regulatory functions of PAX8 in ovarian cancer, an integrative analysis of multi-omic and patient data is required to identify the core regulatory network of PAX8 and its prognostic and therapeutic value. Here, we integrate PAX8 chromatin binding and accessibility data in ovarian cancer cells with transcriptomic and patients' data to gain insight into the core gene regulatory network orchestrated by PAX8 in ovarian tumors. Integration of differential chromatin accessibility, transcription factor binding, and gene expression upon PAX8 knockout provides a core regulatory network that explains most of the genes regulated by PAX8. We combine these target genes with patient expression data and find a PAX8 gene signature associated with tumor stemness, a property related to therapy resistance. Indeed, we show that the PAX8 gene signature predicts disease outcome and response to therapy in ovarian cancer patients. Finally, we validated experimentally our results from bioinformatic analyses, thus reassuring their robustness. Our findings uncover a PAX8 core network that represents a promising strategy for targeted antitumor therapies and open new pathways to fight against ovarian cancer resistance.