APOBEC3A drives ovarian cancer metastasis by altering epithelial-mesenchymal transition

Sep 24, 2026

High-grade serous ovarian cancer (HGSOC) is frequently diagnosed at late stages and is marked by extensive intra- and intertumor heterogeneity, contributing to treatment resistance and relapse. APOBEC3A (A3A), a mutagenic enzyme implicated in cancer progression, was examined in HGSOC. Elevated APOBEC3-mediated mutagenesis correlated with poor overall survival, and A3A expression increased metastatic behavior in culture and distant metastasis in vivo, requiring A3A catalytic activity and producing hybrid EMT and mesenchymal gene signatures. Inhibiting TWIST1 and IL-6 reduced A3A-dependent metastatic phenotypes, supporting A3A as a driver and prognostic biomarker.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Introduction

Clinical context of HGSOC and metastasis

APOBEC3 enzymes and mutagenesis background

APOBEC3 signatures in ovarian cancer

RESE AR CH ARTICLE Conflict of interest: RD is on the Scientific Advisory Board for Repare Therapeutics and is an Advisor for VOC Health. Copyright: © 2025, Devenport et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: August 28, 2024 Accepted: January 22, 2025 Published: January 28, 2025 Reference information: JCI Insight. 2025;10(5):e186409 . [https://doi.org/10.1172/jci](https://doi.org/10.1172/jci). insight.186409 . APOBEC3A drives ovarian cancer metastasis by altering epithelialmesenchymal transition Jessica M. Devenport,1,2 Thi Tran,1 Brooke R. Harris,1 Dylan Fingerman,1,2 Rachel A. DeWeerd,1,2 Lojain H. Elkhidir,1 Danielle LaVigne,1,3 Katherine Fuh,4 Lulu Sun,5 Jeffrey J. Bednarski,1 Ronny Drapkin,6,7 Mary M. Mullen,8 and Abby M. Green1,9 1Department of Pediatrics, 2Cancer Biology Graduate Program, and 3Molecular Genetics and Genomics Graduate Program, Washington University School of Medicine, St. Louis, Missouri, USA. 4Department of Obstetrics, Gynecology, and Reproductive Sciences, UCSF, San Francisco, California, USA. 5Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. 6Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, and 7Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. 8Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Siteman Cancer Center, and 9Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA. 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 ofA3A 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, and this 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-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 IL-6 resulted in mitigation of A3A-dependent metastatic phenotypes. Our findings define the prevalence of A3A mutagenesisin 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 effect of A3A-driven EMT in HGSOC. Introduction Ovarian cancer is the fifth most prevalent cancer among women and is the leading cause of death from gynecologic malignancies worldwide (1) . High-grade serous ovarian cancer (HGSOC) represents the most frequent and aggressive histological subtype of ovarian cancer, accounting for approximately 70%–80% of ovarian cancer-related deaths (2) . HGSOC is often diagnosed at a late stage and exhibits extensive intra-and intertumor heterogeneity, resulting in significant challenges in clinical management (3) . Intratumor heterogeneity in HGSOC manifests as diverse subclones with distinct genomic alterations and gene expression profiles within individual tumors. This clonal diversity is associated with treatment resistance

FAQs

What question does the study address about APOBEC3A in HGSOC?

The study evaluates whether APOBEC3A contributes to HGSOC metastasis and clarifies its role in disease progression, which had not been explored previously.

How was APOBEC3A linked to patient outcomes in primary HGSOC?

Higher levels of APOBEC3-mediated mutagenesis were associated with poor overall survival in primary HGSOC.

What mechanism connects APOBEC3A activity to metastatic behavior?

A3A catalytic activity altered EMT gene expression, producing hybrid EMT/mesenchymal signatures that increased metastatic potential; inhibiting TWIST1 and IL-6 mitigated the A3A-dependent phenotypes.

Sep 24, 2026

Uploaded by Taylor Morgan