# Oxyntic Atrophy and Novel Gastric Lineages

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

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 intr...

## Key facts

- **NIH application ID:** 10086313
- **Project number:** 5I01BX000930-10
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** James Richard Goldenring
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086313

## Citation

> US National Institutes of Health, RePORTER application 10086313, Oxyntic Atrophy and Novel Gastric Lineages (5I01BX000930-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10086313. Licensed CC0.

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