Gastric adenocarcinoma remains the third most common cause of cancer-related death worldwide. The vast majority of gastric cancer evolves in the stomach in the setting of chronic atrophic gastritis usually in association with Helicobacter pylori infection. While the role of H. pylori as the proximate cause of gastric carcinogenesis is well established, the cellular basis of lineage changes that lead to development of preneoplastic metaplasia and progression to cancer remain unclear. Chronic injury associated with H. pylori infection leads to prominent changes in the composition of the gastric epithelia, with loss of parietal cells (oxyntic atrophy), expansion of surface cells (foveolar hyperplasia) and mucous cell metaplasia. Two metaplastic lineages are now acknowledged in the setting of oxyntic atrophy in humans: intestinal metaplasia (characterized by the presence of intestinal goblet cells in the gastric mucosa) and Spasmolytic Polypeptide Expressing Metaplasia (SPEM; characterized by presence of antral type mucous cells in the body of the stomach). However, Helicobacter infection in mice leads only to SPEM. Over the past 20 years, we have investigated the factors that lead to the development of SPEM in the face of oxyntic atrophy. Using lineage- mapping studies in mice, we have demonstrated that SPEM arises, not from professional progenitor cells, but from transdifferentiation of mature Mist1-expressing Chief cells into mucous cell metaplasia. All of these results support the concept that loss of parietal cells from the gastric fundic mucosa induces the development of SPEM from transdifferentiation of Chief cells. Since SPEM appears to be the initial pre-cancerous metaplastic response to oxyntic atrophy, it is critical to understand how transdifferentiation of Chief cells leads to the emergence of SPEM as the central initial event required for the development of dysplasia and neoplasia in the stomach. During the past funding period, we have established that transdifferentiation of Chief cells into SPEM requires an ordered series of cellular events that mediate the downscaling of zymogen granules through autophagy and upscaling of mucous granule production to achieve mucous metaplasia. We have identified discrete interventions that can arrest the process of transdifferentiation through inhibition of the xCT cystine transporter or inhibition of autophagy. We have hypothesized that discrete events mediated by the 14-3-3 protein Stratifin or alterations in miR-148a are critical early triggers for initiating transdifferentiation of Chief cells after severe gastric injury. We will therefore continue our studies of the origin of metaplasia through the prosecution of two specific aims:!!First, we will examine the role of Stratifin in the initiation of reprogramming of chief cells during transdifferentiation into metaplasia. We will seek to evaluate if loss of Stratifin alters the course of transdifferentiation. In addition, we will identify the intracellular phosphoproteins in Chief cells that are targets for Stratifin action. Second, we will determine how miR-148a regulates the initiation and progression of transdifferentiation. We have identified miR-148a as the major miRNA expressed in Chief cells and determined that its expression is rapidly down-regulated at the initiation of transdifferentiation. We will examine the impact of loss of miR-148a on the expression of transcripts and proteins that may mediate transdifferentiation. Validation studies of putative regulators will place these mediators in the context of the discrete steps required for completion of transdifferentiation. ! All of these studies will help identify fundamental mechanisms involved in Chief cell transdifferentiation and may lead to insights in how pre-neoplastic metaplastic lineage changes can be prevented or reversed. !

Public Health Relevance

Gastric cancer is the second most common cause of cancer-related death worldwide. American military actions often expose soldiers to areas with higher prevalence for gastric cancer and increasingly immigrants from high gastric cancer regions in South America are playing a greater role in the US military. Thus, gastric cancer represents a probable increased risk for future Veterans. Given the dismal overall survival for patients with gastric cancer, identification of pre-cancerous lesions and the development of strategies to arrest the progression or even reverse these changes is a high priority. The present proposed investigations seek to establish a greater knowledge of the induction and reversibility of pre-cancerous metaplastic changes in the stomach and evaluate novel approaches to arresting pre-cancerous changes.

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Meyer, Anne R; Goldenring, James R (2018) Injury, repair, inflammation and metaplasia in the stomach. J Physiol 596:3861-3867
Goldenring, James R (2018) Pyloric metaplasia, pseudopyloric metaplasia, ulcer-associated cell lineage and spasmolytic polypeptide-expressing metaplasia: reparative lineages in the gastrointestinal mucosa. J Pathol 245:132-137
Petersen, Christine P; Meyer, Anne R; De Salvo, Carlo et al. (2018) A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach. Gut 67:805-817
Means, Anna L; Freeman, Tanner J; Zhu, Jing et al. (2018) Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer. Cell Mol Gastroenterol Hepatol 6:257-276
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Choi, Eunyoung; Lantz, Tyler L; Vlacich, Gregory et al. (2018) Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach. Gut 67:1595-1605
Burclaff, Joseph; Osaki, Luciana H; Liu, Dengqun et al. (2017) Targeted Apoptosis of Parietal Cells Is Insufficient to Induce Metaplasia in Stomach. Gastroenterology 152:762-766.e7
Jeong, Sangho; Choi, Eunyoung; Petersen, Christine P et al. (2017) Distinct metaplastic and inflammatory phenotypes in autoimmune and adenocarcinoma-associated chronic atrophic gastritis. United European Gastroenterol J 5:37-44
Mills, Jason C; Goldenring, James R (2017) Metaplasia in the Stomach Arises From Gastric Chief Cells. Cell Mol Gastroenterol Hepatol 4:85-88
Goldenring, James R; Mills, Jason C (2017) Isthmus Time Is Here: Runx1 Identifies Mucosal Stem Cells in theĀ Gastric Corpus. Gastroenterology 152:16-19

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