High-grade serous ovarian cancer (HGSOC), the most lethal gynecologic malignancy, frequently carries mutational signatures (SBS2/SBS13) produced by the cytidine deaminase APOBEC3A (A3A). Devenport and colleagues showed that episodic A3A activity in HGSOC models induces hybrid epithelial/mesenchymal (E/M) and mesenchymal transcriptional programs, IL-6 secretion, and metastatic spread in a deaminase-dependent manner, and that IL-6 receptor blockade with tocilizumab mitigated the A3A-dependent metastatic phenotypes, implicating IL-6 signaling downstream of A3A. However, the study could not explain how A3A enzymatic activity is causally converted into these EMT transcriptional changes: recurrent mutations did not account for them, and several candidate routes remain untested. The open problem is to identify the molecular mechanism(s) linking A3A deaminase activity to EMT gene-expression programs in HGSOC and to determine whether these alterations persist without ongoing A3A activity.

Background

The APOBEC3 (A3) proteins are a family of innate-immune cytidine deaminases that convert cytosine to uracil in single-stranded DNA and RNA. When misexpressed in tumor cells, their activity leaves characteristic mutational footprints in cancer genomes, known as the single-base-substitution signatures SBS2 and SBS13, and APOBEC3A (A3A) is considered the predominant contributor to these signatures in many tumor types. High-grade serous ovarian cancer (HGSOC) is the most common and aggressive histological subtype of ovarian cancer and usually presents with widely metastatic disease; its metastatic drivers remain incompletely understood. Epithelial–mesenchymal transition (EMT) is a developmental program in which epithelial tumor cells lose adhesion and acquire migratory and invasive properties; cells can also adopt stable hybrid epithelial/mesenchymal (E/M) states associated with aggressive behavior. Interleukin-6 (IL-6), a pro-inflammatory cytokine secreted by tumor and stromal cells, is an established inducer of EMT-like states in ovarian cancer. Devenport et al. (2025) analyzed whole-genome sequencing of primary HGSOC and found APOBEC3 mutagenesis enriched in metastatic sites and associated with poor overall survival. Modeling episodic A3A expression in HGSOC cell lines and mouse xenografts (tumors grown from implanted human tumor cells) increased migratory behavior and distant metastatic spread, and produced hybrid E/M and mesenchymal gene-expression signatures both in cultured cells and in metastatic patient tumors; the effect required A3A catalytic activity, since a deaminase-defective A3A mutant failed to promote metastatic phenotypes — a notable contrast with a prior report that A3A promotes pancreatic cancer metastasis through deaminase-independent chromosomal instability (Wörmann et al. 2021). A3A exposure also upregulated IL-6 expression and secretion, and blocking the IL-6 receptor with tocilizumab reversed the migratory phenotype in these assays, supporting the source's proposed model in which IL-6 signaling acts downstream of A3A and upstream of the EMT program; this is pharmacological evidence in these cell lines rather than a genetic demonstration that IL-6 is an obligatory intermediate. The mechanistic gap is the upstream link: the observed transcriptional changes were not explained by recurrent genomic mutations in the affected genes. Biochemical and functional literature supports several candidate routes, none of which has been demonstrated in HGSOC: A3A efficiently deaminates 5-methylcytosine (the methylated cytosine that carries DNA methylation marks) to thymine, providing a plausible enzymatic route to localized loss of DNA methylation with consequences for chromatin accessibility and gene expression (Wijesinghe and Bhagwat 2012; Carpenter et al. 2012; Schutsky et al. 2017); A3A can bind TTTC motifs within interferon-stimulated response elements (ISREs, promoter motifs that drive interferon-inducible genes) and repress transcription from them, suggesting direct regulatory-DNA binding as a non-deaminating mode of transcriptional control (Taura et al. 2022); and the related enzyme APOBEC3B promotes local chromatin remodeling at estrogen-receptor binding sites in breast cancer through deamination-triggered DNA breaks and repair (Periyasamy et al. 2015), a damage-coupled mechanism A3A could plausibly share. Which of these mechanisms, alone or in combination, actually converts A3A activity into EMT transcriptional programs in HGSOC is unknown, as is whether such programs, once established, are durable without continuing A3A activity.

Problem Statement

By what molecular mechanism(s) does APOBEC3A deaminase activity elicit epithelial–mesenchymal transition (EMT) transcriptional programs — including upregulation of IL-6 — in high-grade serous ovarian cancer, given that recurrent genomic mutations do not explain the observed gene-expression changes? The source work discusses candidate routes as hedged possibilities, without excluding other mechanisms: A3A-mediated deamination of 5-methylcytosine leading to epigenetic and chromatin-accessibility alterations; direct A3A binding to regulatory DNA elements affecting transcriptional control (analogous to its binding of TTTC motifs in interferon-stimulated response elements); DNA-damage- and repair-associated local chromatin remodeling; and creation or disruption of transcription-factor binding sites. A closely related question posed explicitly by the source is whether the A3A-driven transcriptional alterations are durable in the absence of ongoing A3A expression or activity. The source further notes, as a future direction enabled by the work rather than as a posed open question, studying whether the same A3A-to-EMT axis operates in other tumor types where APOBEC3 mutagenesis is prevalent.

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