Adenocarcinoma in the human stomach evolves in the setting of Helicobacter pylori-induced oxyntic atrophy and chronic mucous cell metaplasia. Our lab demonstrated that metaplasia in the gastric fundus in mice does not arise from the professional progenitor cells located in the upper neck region of the glands, but rather develops from transdifferentiation of mature chief cells into Spasmolytic Polypeptide Expressing Metaplasia, or SPEM. These studies have led to a significant paradigm shift in the concepts for the origin of gastric neoplasia, suggesting that pre-neoplastic lineages do not arise from professional resident mucosal progenitor cell populations, but rather develop from transdifferentiation of mature zymogenic cell lineages. Furthermore, multiple studies now indicate that SPEM develops both increased proliferation and increasing levels of intestinalizing gene expression in the setting of inflammation, and in humans gives rise to goblet cell intestinal metaplasia. My recent investigations have demonstrated that macrophages are responsible for the promotion of proliferative SPEM progression, but the precise mediators that are responsible for the progression of SPEM towards intestinalization and dysplasia remain unknown. I therefore hypothesize that discrete intrinsic mucosal and macrophage-derived factors regulate not only the evolution, but also the progression of SPEM to more proliferative, preneoplastic metaplasia. To address this hypothesis, I will pursue two specific aims: First, I will examine the characteristics of macrophages associated with the evolution and progression of metaplasia in the mouse stomach by isolating macrophages for RNA sequencing analysis. Second, using isolated macrophages and a novel ImSPEM cell line, I will examine mechanistically how macrophages influence the progression of metaplasia in vitro. Overall, the present investigations focus on the inflammatory cell mechanisms that might drive metaplasias to preneoplasia in the stomach.
Metaplasias are the major precursor lesions for gastric cancer. This proposal seeks to understand the induction and progression of metaplasia towards cancer and how an understanding of pre-cancerous lesions can lead to improved approaches for early detection and treatment.