Friday, May 9, 2025
5/9/2025
The double-stranded RNA (dsRNA) response in gastric pre-neoplasia - PROJECT SUMMARY / ABSTRACT Gastric cancer is a leading cause of cancer-related deaths worldwide and carries a dismal prognosis in the United States. A critical pre-neoplastic stage and determinant of oncogenic risk is the development of pyloric metaplasia. However, we still have a limited understanding of how pyloric metaplasia develops and expands in the setting of chronic inflammation. My laboratory’s long-term goal is to characterize new and potentially targetable pathways in pyloric metaplasia. We recently and unexpectedly identified the response to double-stranded RNA (dsRNA) as the most upregulated pathway across two distinct models of murine pyloric metaplasia. dsRNA signaling was initially described as an innate immune response that induces type I interferons (IFNαβ) during viral infection. Its role in gastric pre-neoplasia had not been studied, however. Our previous work confirmed that dsRNA accumulates in metaplastic gastric epithelium in germ-free mice and in humans, and recent evidence indirectly suggests that the response to dsRNA is downregulated in human gastric cancer. dsRNA signaling therefore represents an under-appreciated pathway in gastric epithelial injury and tumorigenesis. The objective of this proposal is to establish how dsRNA signaling contributes to gastric pre-neoplasia. To address this, we specifically deleted a central regulator of dsRNA signaling, ADAR1, from gastric parietal cells (Adar1ΔPC). Consistent with a role for dsRNA signaling in pre-neoplasia, Adar1ΔPC mice spontaneously developed pyloric metaplasia and gastric dysplasia. Further molecular characterization found that mitochondrial RNA (mt- RNA) accumulated within the gastric epithelium of Adar1ΔPC stomachs, implicating mt-RNA as a potential trigger of epithelial dsRNA signaling. Single-cell RNA sequencing and flow cytometric analyses demonstrated a sustained and transcriptionally upregulated dsRNA response throughout the gland that was independent of adaptive immunity. We have therefore developed a tractable model of gastric pre-neoplasia that we will use to understand how dsRNA signaling promotes a pre-cancerous gastric environment. Aim 1 will examine how distinct sources of dsRNA activate dsRNA signaling within gastric epithelium, using an established gastroid system, new murine models, and innovative in vitro approaches. Aim 2 will rely on genetic mouse models and bone marrow chimera experiments to determine how epithelium- and immune-mediated IFNαβ signaling connects the dsRNA response to gastric pre-neoplasia. The proposed experiments are logical extensions of our previous work. They also establish new foundational tools and exciting research avenues that can be completed within the award period. The importance of this application is to enhance our mechanistic understanding of a previously unexplored and therapeutically targetable pathway in gastric pre-neoplasia that can be broadly applied to pre-neoplastic states across other epithelial tissues.
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