APOBEC3A drives ovarian cancer metastasis by altering epithelial-mesenchymal transition
Jessica M. Devenport, … , Mary M. Mullen, Abby M. Green
Jessica M. Devenport, … , Mary M. Mullen, Abby M. Green
Published March 10, 2025
Citation Information: JCI Insight. 2025;10(5):e186409. https://doi.org/10.1172/jci.insight.186409.
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Research Article Cell biology Oncology

APOBEC3A drives ovarian cancer metastasis by altering epithelial-mesenchymal transition

Abstract

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, 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 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 effect of A3A-driven EMT in HGSOC.

Authors

Jessica M. Devenport, Thi Tran, Brooke R. Harris, Dylan Fingerman, Rachel A. DeWeerd, Lojain H. Elkhidir, Danielle LaVigne, Katherine Fuh, Lulu Sun, Jeffrey J. Bednarski, Ronny Drapkin, Mary M. Mullen, Abby M. Green

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Figure 1

APOBEC3 activity correlates with poor survival in patients with HGSOC.

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APOBEC3 activity correlates with poor survival in patients with HGSOC. (...
(A) Whole genome sequencing was assessed to determine the mutational processes occurring within tumor genomes from PCAWG Ovarian Cancer (PCAWG), TCGA Ovarian Cancer (TCGA), and Dana Farber Cancer Institute/University of Pennsylvania (DFCI/PENN) patient cohorts. Relative contribution of APOBEC3 mutational signatures (SBS2 and SBS13) is shown as a fraction of total mutational burden (PCAWG, 5.9%; TCGA, 4.9%; DFCI/PENN, 7.3%). (B–E) Whole exome sequencing from a patient cohort at Washington University in St. Louis (WUSTL), which includes matched metastatic (M) and primary (P) samples, was assessed for relative contribution of SBS2 and SBS13 (B). For patients with metastatic sites that demonstrated > 4% relative contribution (upper quartile) of SBS2 and SBS13 (patient nos. 4, 7, 14, 15, 17, 18), paired P and M SBS2 and SBS13 fractions are shown. (C) Survival of patients with tumors designated as APOBEC3 high (>4%) versus low (<4%). (D) Patients were grouped by long-term (>5 years) and short-term (<3.5 years) survival. The relative contribution of SBS2+13 in metastatic sites relative to matched primary is shown for individual patients as a heatmap. (E) Analysis of relative contribution of SBS2 and SBS13 shows increased SBS2+13 in primary and metastatic sites for individual patients is shown. Blue dots are from patients with short-term survival, and purple dots represent patients with long-term survival. Statistical significance was determined by uncorrected Fisher’s test, P = 0.02. (F) Genomic assessment of multisite biopsies from patients in the DFCI/PENN cohort. Seven patients with >4% SBS2 and SBS13 relative contribution are shown. Relative contribution of SBS2 and SBS13 shown for each biopsy site ranging from precursor lesions (p53 signatures, serous tubal intraepithelial carcinoma [STIC]) to metastatic sites. Three patients had biopsies of only STIC lesions (64, 65) (patient genome 304). Unlabeled circles and arrows between lesions indicate inferred subclonal hierarchy, adapted from Labidi-Galy, et al. (41), and predicted progression of disease.