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APOBEC3A Promotes the Metastatic Progression of High-Grade Serous Ovarian Carcinoma by Altering Epithelial-Mesenchymal Trajectories
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APOBEC3A Promotes the Metastatic Progression of High-Grade Serous Ovarian Carcinoma by Altering Epithelial-Mesenchymal Trajectories
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Dissertation
APOBEC3A Promotes the Metastatic Progression of High-Grade Serous Ovarian Carcinoma by Altering Epithelial-Mesenchymal Trajectories
2025
Overview
High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive histological subtype of ovarian cancer, and often presents with metastatic disease. The drivers of metastasis in HGSOC remain enigmatic. APOBEC3A (A3A), an enzyme that generates mutations across various cancers, has been proposed as a mediator of tumor heterogeneity and disease progression. However, the role of A3A in HGSOC has not been explored. We observed an association between high levels of APOBEC3-mediated mutagenesis and poor overall survival in primary HGSOC. We experimentally addressed this correlation by modeling A3A expression in HGSOC which resulted in increased metastatic behavior of HGSOC cells in culture and distant metastatic spread in vivo, which was dependent on catalytic activity of A3A. A3A activity in both primary and cultured HGSOC cells yielded consistent alterations in expression of epithelial-to-mesenchymal transition (EMT) genes resulting in hybrid EMT and mesenchymal signatures, providing a mechanism for their increased metastatic potential. Inhibition of key EMT factors TWIST1 and interleukin-6 (IL-6) resulted in mitigation of A3A-dependent metastatic phenotypes. Our findings define the prevalence of A3A mutagenesis in HGSOC and implicate A3A as a driver of HGSOC metastasis via EMT, underscoring its clinical relevance as a potential prognostic biomarker. Our study lays the groundwork for the development of targeted therapies aimed at mitigating the deleterious impact of A3A-driven EMT in HGSOC.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9798314859971
