1. Notch signaling drives development of Barrett's metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa.
- Author
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Kunze B, Middelhoff M, Maurer HC, Agibalova T, Anand A, Bührer AM, Fang HY, Baumeister T, Steiger K, Strangmann J, Schmid RM, Wang TC, and Quante M
- Subjects
- Adenocarcinoma metabolism, Animals, Carcinogenesis metabolism, Cardia metabolism, Cell Differentiation physiology, Cell Proliferation physiology, Disease Models, Animal, Esophageal Neoplasms metabolism, Esophagus metabolism, Mice, Stem Cells metabolism, Wnt Signaling Pathway physiology, Barrett Esophagus metabolism, Doublecortin-Like Kinases metabolism, Epithelial Cells metabolism, Gastric Mucosa metabolism, Metaplasia metabolism, Receptors, Notch metabolism, Signal Transduction physiology
- Abstract
Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development.
- Published
- 2021
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