Jag1/2 maintain esophageal homeostasis and suppress foregut tumorigenesis by restricting the basal progenitor cell pool

Haidi Huang, Yu Jiang, Jiangying Liu, Dan Luo, Jianghong Yuan, Rongzi Mu, Xiang Yu, Donglei Sun, Jihong Lin, Qiyue Chen, Xinjing Li, Ming Jiang, Jianming Xu, Bo Chu, Chengqian Yin, Lei Zhang, Youqiong Ye, Bo Cao, Qiong Wang () and Yongchun Zhang ()
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Haidi Huang: Shanghai Jiao Tong University
Yu Jiang: Shanghai Jiao Tong University
Jiangying Liu: Shanghai Jiao Tong University
Dan Luo: Shanghai Jiao Tong University
Jianghong Yuan: Shanghai Jiao Tong University
Rongzi Mu: Shanghai Jiao Tong University
Xiang Yu: Shanghai Jiao Tong University
Donglei Sun: Shanghai Jiao Tong University
Jihong Lin: Fujian Medical University Union Hospital
Qiyue Chen: Fujian Medical University Union Hospital
Xinjing Li: Shanghai Jiao Tong University
Ming Jiang: Zhejiang University School of Medicine
Jianming Xu: Baylor College of Medicine
Bo Chu: Shandong University
Chengqian Yin: Shenzhen Bay Laboratory
Lei Zhang: Shenzhen Bay Laboratory
Youqiong Ye: Shanghai Jiao Tong University School of Medicine
Bo Cao: Shanghai Jiao Tong University
Qiong Wang: Shanghai Jiao Tong University School of Medicine
Yongchun Zhang: Shanghai Jiao Tong University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and accelerates the initiation of squamous cell carcinoma (SCC) in the forestomach. Importantly, expression levels of JAG1/2 are lower in the early stages of human esophageal squamous cell carcinoma (ESCC) carcinogenesis. Collectively, our study demonstrates that Jag1/2 are important for maintaining esophageal and forestomach homeostasis and the onset of foregut SCC.

Date: 2024
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DOI: 10.1038/s41467-024-48347-5

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