Notch signaling drives development of Barrett’s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa
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
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Notes
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Scientific reports. - 11, 1 (2021) , 4509, ISSN: 2045-2322
- Event
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Veröffentlichung
- (where)
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Freiburg
- (who)
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Universität
- (when)
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2021
- Creator
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Kunze, Bettina
Middelhoff, Moritz
Maurer, H. Carlo
Agibalova, Tatiana
Anand, Akanksha
Bührer, Anne-Marie
Fang, Hsin-Yu
Baumeister, Theresa
Steiger, Katja
Strangmann, Julia
Schmid, Roland M.
Wang, Timothy C.
Quante, Michael
- DOI
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10.1038/s41598-021-84011-4
- URN
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urn:nbn:de:bsz:25-freidok-1936633
- Rights
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Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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15.08.2025, 7:27 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Kunze, Bettina
- Middelhoff, Moritz
- Maurer, H. Carlo
- Agibalova, Tatiana
- Anand, Akanksha
- Bührer, Anne-Marie
- Fang, Hsin-Yu
- Baumeister, Theresa
- Steiger, Katja
- Strangmann, Julia
- Schmid, Roland M.
- Wang, Timothy C.
- Quante, Michael
- Universität
Time of origin
- 2021
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