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 ( Adar1 ^ΔPC ). Adar1 ^ΔPC and age-matched controls stomachs were histologically, transcriptionally, and immunologically profiled. The source of dsRNA in Adar1 ^ΔPC gastric epithelium was assessed by dsRNA immunoprecipitation and immuno-electron microscopy. Finally, to define the contributions of interferon (IFN) signaling, Adar1 ^ΔPC ;Ifnar1 ^-/- and Adar1 ^ΔPC ;Ifnlr1 ^-/- mice, defective in type I and type III IFN signaling, respectively, were characterized. Results Adar1 ^ΔPC 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 Adar1 ^ΔPC stomachs. Conclusions Our new genetic model implicates ADAR1-mediated dsRNA signaling in gastric pre-neoplasia.