Ménétrier’s disease is an uncommonly acquired hypoproteinemic hypertrophic gastropathy. Patients present with a constellation of progressive signs and symptoms that include severe abdominal pain, unremitting nausea and vomiting, peripheral edema (due to loss of protein across the gastric mucosa) and achlorhydria (due to loss of acid-producing parietal cells), along with an increased risk of gastric cancer. Until recently, gastrectomy has been the only therapeutic option. Increased EGFR signaling has been implicated in the pathogenesis of Ménétrier’s disease. The EGFR ligand, transforming growth factor-α (TGF-α is overexpressed in the gastric mucosa of Ménétrier’s disease patients, and transgenic mice that overexpress TGF-α in the stomach phenocopy many of the features of Ménétrier’s disease. We have discovered that Notch signaling is upregulated and is downstream of EGFR signaling in patients with Ménétrier’s disease and MT-TGF-α mice. We are focused to better understand the underlying mechanisms of Ménétrier’s disease and optimize treatment regimens that can be advanced to a clinical trial.
Tissue injury induces terminally differentiated cells to reprogram and reenter the cell cycle to facilitate regeneration. In the stomach, spasmolytic-polypeptide-expressing metaplasia (SPEM) occurs following injury and these cells fuel regeneration. However, SPEM is also a precancerous lesion in the stomach. It has been shown that chief cells are the major source for SPEM and we have shown that SPEM cells can repopulate other cell types during the recovery. We are now testing if other cell types (e.g., parietal cells) can reprogram to SPEM and function as quiescent stem/progenitor cells. We are focused to investigate signal pathways that regulate these cells’ plasticity in the stomach and find targets of treatment to facilitate regeneration and inhibit tumorigenesis.
We have observed that male mice express two- to three-fold higher EGFR protein in their livers compared to female mice. Notably, this sex difference in hepatic EGFR levels extends to humans. In mice, we have found that EGFR levels in the liver are regulated by testosterone. We are focused to investigate whether testosterone also regulates EGFR expression in human liver, the mechanism how testosterone regulates EGFR, and the effects of sex differential expression of hepatic EGFR on the male predominance of fatty liver disease and hepatocellular carcinoma.