A pSMAD/CDX2 Complex Is Essential for the Intestinalization of Epithelial Metaplasia

•Overexpression of BMP4 in the esophageal epithelium of mice leads to columnar metaplasia•Induced reflux sequentially induces nonintestinal and intestinal metaplasia•Coexpression of BMP4 and CDX2 in epithelial cells induces specific intestinal genes•pSMAD and CDX2 form a complex required for the development of intestinal metaplasia

SummaryThe molecular mechanisms leading to epithelial metaplasias are poorly understood. Barrett's esophagus is a premalignant metaplastic change of the esophageal epithelium into columnar epithelium, occurring in patients suffering from gastroesophageal reflux disease. Mechanisms behind the development of the intestinal subtype, which is associated with the highest cancer risk, are unclear. In humans, it has been suggested that a nonspecialized columnar metaplasia precedes the development of intestinal metaplasia. Here, we propose that a complex made up of at least two factors needs to be activated simultaneously to drive the expression of intestinal type of genes. Using unique animal models and robust in vitro assays, we show that the nonspecialized columnar metaplasia is a precursor of intestinal metaplasia and that pSMAD/CDX2 interaction is essential for the switch toward an intestinal phenotype.

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