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....

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Autores principales:	Bettina Kunze, Moritz Middelhoff, H. Carlo Maurer, Tatiana Agibalova, Akanksha Anand, Anne-Marie Bührer, Hsin-Yu Fang, Theresa Baumeister, Katja Steiger, Julia Strangmann, Roland M. Schmid, Timothy C. Wang, Michael Quante
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9272e2c5e4364d47ad3c73c83b1fbcaa
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spelling	oai:doaj.org-article:9272e2c5e4364d47ad3c73c83b1fbcaa2021-12-02T15:52:59ZNotch signaling drives development of Barrett’s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa10.1038/s41598-021-84011-42045-2322https://doaj.org/article/9272e2c5e4364d47ad3c73c83b1fbcaa2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84011-4https://doaj.org/toc/2045-2322Abstract 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.Bettina KunzeMoritz MiddelhoffH. Carlo MaurerTatiana AgibalovaAkanksha AnandAnne-Marie BührerHsin-Yu FangTheresa BaumeisterKatja SteigerJulia StrangmannRoland M. SchmidTimothy C. WangMichael QuanteNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Bettina Kunze Moritz Middelhoff H. Carlo Maurer Tatiana Agibalova Akanksha Anand Anne-Marie Bührer Hsin-Yu Fang Theresa Baumeister Katja Steiger Julia Strangmann Roland M. Schmid Timothy C. Wang Michael Quante Notch signaling drives development of Barrett’s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa
description	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.
format	article
author	Bettina Kunze Moritz Middelhoff H. Carlo Maurer Tatiana Agibalova Akanksha Anand Anne-Marie Bührer Hsin-Yu Fang Theresa Baumeister Katja Steiger Julia Strangmann Roland M. Schmid Timothy C. Wang Michael Quante
author_facet	Bettina Kunze Moritz Middelhoff H. Carlo Maurer Tatiana Agibalova Akanksha Anand Anne-Marie Bührer Hsin-Yu Fang Theresa Baumeister Katja Steiger Julia Strangmann Roland M. Schmid Timothy C. Wang Michael Quante
author_sort	Bettina Kunze
title	Notch signaling drives development of Barrett’s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa
title_short	Notch signaling drives development of Barrett’s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa
title_full	Notch signaling drives development of Barrett’s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa
title_fullStr	Notch signaling drives development of Barrett’s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa
title_full_unstemmed	Notch signaling drives development of Barrett’s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa
title_sort	notch signaling drives development of barrett’s metaplasia from dclk1-positive epithelial tuft cells in the murine gastric mucosa
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9272e2c5e4364d47ad3c73c83b1fbcaa
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Notch signaling drives development of Barrett’s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa

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