Oxyntic Atrophy and Novel Gastric Lineages.

Background and innovation: Intestinal type gastric cancer arises within a carcinogenic cascade from pre- cancerous metaplasia to dysplasia and adenocarcinoma. Pyloric metaplasia in the stomach corpus develops as a reparative lineage following parietal cell loss through the plasticity of normal chief cells to transdifferentiate into spasmolytic polypeptide-expressing metaplasia (SPEM) cells in response to mucosal injury. Progression to high-risk gastric incomplete intestinal metaplasia and dysplasia can occur within a field of reparative metaplasia, especially in the context of chronic inflammation. Our studies over the past decade have indicated that induction and progression of metaplasia is driven by continued activation of the Ras signaling pathway. Inhibition of the Ras pathway with inhibitors of MEK leads to arrest of metaplasia and reprogramming the mucosa with return of normal gastric lineages. These studies have led to the innovative concept that therapeutic reprogramming can abrogate the risk of developing gastric cancer. In addition, our most recent studies have revealed two important insights: First, Pyrvinium can both arrest metaplasia and induce cell death in dysplastic cells through inhibition of both ERK1/2 phosphorylation and STAT3 phosphorylation. Thus, treatment with Pyrvinium leads to both arrest of metaplasia and the death of dysplastic cells. Given the long history of Pyrvinium as a benign drug used to treat pinworm in children, Pyrvinium may represent a superior and safe therapeutic intervention for reprogramming the gastric mucosa. Second, we have found that fibroblasts in the metaplastic and dysplastic milieu promote the conversion of metaplastic lineages to dysplasia. Our preliminary studies have demonstrated that this fibroblast influence is mediated through the secretion of Spondin 2 (SPON2), which may act as a putative activator of STAT3. We hypothesize that activation of both the ERK and STAT3 pathways is critical for dysplastic transition from metaplasia. To examine this hypothesis, we will pursue two specific aims: First, we will determine the role of Spondin 2 (SPON2) in promoting progression of metaplasia to dysplasia. We will seek to determine whether fibroblast- derived SPON2 is responsible promotion of dysplastic transition in metaplastic human gastroids. We will examine whether SPON2 alters ERK1/2 and/or STAT3 phosphorylation and identify the receptor for SPON2 on metaplastic gastroid cells. Second, to optimize pre-clinical studies we will examine the onset of ERK1/2 and STAT3 phosphorylation changes and specific lineage changes in association with reprogramming of the metaplastic mucosa and determine the durability of short-term Pyrvinium treatment. Furthermore, we will evaluate Pyrvinium and Pyrvinium analogs for their ability to induce death in dysplastic gastroids. Significance and impact to Veteran Health: While the incidence of gastric cancer in the United States is relatively low, it is extremely high in Asia and South America. The high regional incidence of gastric cancer is of particular interest for the large number of recent immigrants to the United States from Mexico and South America, who represent an increasingly important group of recruits for military service. These trends suggest that this Latino/Hispanic group will be especially susceptible to gastric cancer development over the next 20 years. In addition, recent studies have identified an alarming increase in gastric cancer among young women. Thus, gastric cancer will become an increasing concern for the United States and the Veteran population. Pathway to translation: These studies will allow identification of novel more potent compounds for therapeutic reprogramming of metaplasia and dysplasia. The results will facilitate testing of Pyrvinium and/or its analogs for utility in arresting metaplasia and eliminating dysplasia in the Mist1-Kras mouse model of induced metaplasia and dysplasia. Overall, this study will develop pre-clinical support for the use of limited duration therapeutic interventions that can eliminate high-risk pre-cancerous lesions and thereby reduce patient risks for developing cancer.