Notch signaling drives development of Barrett's metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa.
Adenocarcinoma
/ metabolism
Animals
Barrett Esophagus
/ metabolism
Carcinogenesis
/ metabolism
Cardia
/ metabolism
Cell Differentiation
/ physiology
Cell Proliferation
/ physiology
Disease Models, Animal
Doublecortin-Like Kinases
/ metabolism
Epithelial Cells
/ metabolism
Esophageal Neoplasms
/ metabolism
Esophagus
/ metabolism
Gastric Mucosa
/ metabolism
Metaplasia
/ metabolism
Mice
Receptors, Notch
/ metabolism
Signal Transduction
/ physiology
Stem Cells
/ metabolism
Wnt Signaling Pathway
/ physiology
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
24 02 2021
24 02 2021
Historique:
received:
20
10
2020
accepted:
08
02
2021
entrez:
25
2
2021
pubmed:
26
2
2021
medline:
15
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33627749
doi: 10.1038/s41598-021-84011-4
pii: 10.1038/s41598-021-84011-4
pmc: PMC7904766
doi:
Substances chimiques
Receptors, Notch
0
Doublecortin-Like Kinases
EC 2.7.1.11
Dclk1 protein, mouse
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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