A New Model of Gastric Pre-neoplasia Induced by Aberrant ADAR1-mediated Double-stranded RNA Signaling.

BACKGROUND & AIMS: Recent evidence suggests that endogenously derived double-stranded RNA (dsRNA) impacts multiple cellular processes, although its role in epithelial injury remains understudied. We previously identified the response to dsRNA as the most upregulated pathway across 2 distinct murine models of spasmolytic polypeptide-expressing metaplasia (SPEM), a critical pre-neoplastic transition in the progression to gastric cancer. The aim of this study was to define how dysregulation of the dsRNA response within gastric epithelium impacts gastric pre-neoplasia. METHODS: We specifically deleted ADAR1, a central regulator of dsRNA signaling, from gastric parietal cells (Adar1ΔPC). Adar1ΔPC and age-matched controls stomachs were histologically, transcriptionally, and immunologically profiled. The source of dsRNA in Adar1ΔPC gastric epithelium was assessed by dsRNA immunoprecipitation and immuno-electron microscopy. Finally, to define the contributions of interferon (IFN) signaling, Adar1ΔPC;Ifnar1-/-and Adar1ΔPC;Ifnlr1-/- mice, defective in type I and type III IFN signaling, respectively, were characterized. RESULTS: Adar1ΔPC mice spontaneously developed SPEM and gastric dysplasia, in the absence of exogenous injury. Our phenotype depended on Mavs, a key dsRNA signaling hub, implying that our model of gastric pre-neoplasia was specific to dsRNA signaling. Further characterization of this pre-neoplastic environment by single-cell RNA sequencing and flow cytometry noted a chronic and sustained transcriptional upregulation of the dsRNA response throughout gastric epithelium that was independent of adaptive immunity and that depended on both type I and type III IFN signaling. Finally, we identified an enrichment of mitochondrial dsRNA within the gastric epithelium of Adar1ΔPC stomachs. CONCLUSIONS: Our new genetic model implicates ADAR1-mediated dsRNA signaling in gastric pre-neoplasia.