APOBEC3A drives ovarian cancer metastasis by altering epithelial-mesenchymal transition
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
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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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 5

Episodic A3A alters epithelial-mesenchymal transition in HGSOC.

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Episodic A3A alters epithelial-mesenchymal transition in HGSOC. (A) RNA-...
(A) RNA-Seq from OVCAR4 and OVCAR3 A3A V1–V3 and NT parental cell lines was performed. Gene set enrichment analysis (GSEA) of the significant differentially expressed genes (DEGs) between A3A-exposed and NT cells demonstrated that the most significantly enriched MSigDB Hallmark gene set for each version was Hallmark EMT. Significance determined by FDR q value. Color and size of bubbles in plot indicates number of DEGs identified in the Hallmark EMT gene set (out of 200 genes total in gene set) for each A3A-exposed cell line. (B) RNA-Seq from the WUSTL patient cohort was analyzed to determine DEGs between metastatic samples with low (<4%) or high (>4%) contribution of APOBEC3 mutational signatures. Significantly different gene sets were determined by FDR q value. Color and size of bubbles in plot indicates number of DEGs identified in each significant Hallmark gene set. (C) DEGs were assessed using the Tagliazucchi EMT trajectory score (38) to define epithelial (Epi.), hybrid (hEMT), and mesenchymal (Mes.) macrostates in each cell line. A3A V1–V3 for both cell lines are grouped together. Violin plots show the score for each EMT category. Values less than 0 indicate underrepresented gene groups. Significance determined by Brown-Forsythe and Welch 1-way ANOVA with Dunnett’s T3 correction for multiple comparison. *P ≤ 0.05. (D) Bar graph showing the DEGs in OVCAR-A3A cells found in the Tagliazucchi EMT trajectory score. (E) The Tagliazucchi EMT trajectory was applied to DEGs from metastatic tumors from WUSTL cohort patients with APOBEC3 high versus low mutational burdens. Violin plots show the score for each EMT category. Values less than 0 indicate underrepresented gene groups. Significance determined by 2-tailed t-test. **P ≤ 0.01. (F) Bar graph of WUSTL cohort DEGs from the Tagliazucchi EMT trajectory score.