Notch signaling drives development of Barrett's metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa.
Notch signaling drives development of Barrett's metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa.
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Notch信号驱动小鼠胃粘膜中Dclk1阳性上皮丛细胞的Barrett化生。
DOI：
10.1038/s41598-021-84011-4
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发表时间：
2021-02-24
影响因子：
4.6
通讯作者：
Quante M
中科院分区：
文献类型：
--
作者：
Kunze B;Middelhoff M;Maurer HC;Agibalova T;Anand A;Bührer AM;Fang HY;Baumeister T;Steiger K;Strangmann J;Schmid RM;Wang TC;Quante M
Barrett食管（BE）是食管腺癌（EAC）的前体，但其细胞起源和肿瘤进展的机制尚未解决。Notch信号传导在调节肠道干细胞维持中起关键作用，与许多癌症有关。激酶Dclk 1标记鳞状-柱状连接（SCJ）处的上皮有丝分裂后簇细胞，并且也被认为有助于上皮肿瘤生长。在此，我们发现上皮Dclk 1阳性簇细胞中细胞内Notch信号的遗传激活导致BE小鼠模型（pL2.Dclk1.N2IC小鼠）中化生和发育不良的加速发展。相反，在Dclk 1阳性细胞中Notch受体2的基因消融延迟BE进展（pL2.Dclk1.N2fl小鼠），并导致分泌细胞分化增加。在pL2.Dclk1.N2IC小鼠中加速的BE进展与转录组学景观的变化相关，最显著的是BE组织中致癌、增殖途径的激活，与pL2.Dclk1.N2fl小鼠中上调的Wnt信号传导相反。总的来说，我们的数据表明，在贲门Dclk 1阳性簇细胞的Notch激活可以有助于BE的发展。
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.
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影响因子：
29.4
作者：
Huh WJ;Khurana SS;Geahlen JH;Kohli K;Waller RA;Mills JC
通讯作者：
Mills JC
DOI：
10.1084/jem.20061442
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Besseyrias V;Fiorini E;Strobl LJ;Zimber-Strobl U;Dumortier A;Koch U;Arcangeli ML;Ezine S;Macdonald HR;Radtke F
通讯作者：
Radtke F
影响因子：
4.6
作者：
Andreu, P;Colnot, S;Romagnolo, B
通讯作者：
Romagnolo, B
影响因子：
64.8
作者：
Gerbe F;Sidot E;Smyth DJ;Ohmoto M;Matsumoto I;Dardalhon V;Cesses P;Garnier L;Pouzolles M;Brulin B;Bruschi M;Harcus Y;Zimmermann VS;Taylor N;Maizels RM;Jay P
通讯作者：
Jay P
影响因子：
2.5
作者：
Bezencon, C.;Fuerholz, A.;Damak, S.
通讯作者：
Damak, S.