Wnt信号通路
间质细胞
胰腺癌
癌症研究
生物
谷氨酰胺
肝星状细胞
基因敲除
细胞生长
下调和上调
连环素
癌细胞
内分泌学
信号转导
内科学
细胞生物学
细胞培养
癌症
生物化学
医学
基因
氨基酸
遗传学
作者
Hangqi Liu,Hui Zhang,Xiaoqian Liu,Wei Guo,Qiaofei Liu,Longyun Chen,Junyi Pang,Xiaoding Liu,Ruiyu Li,Wei‐Min Tong,Huanwen Wu,Menghua Dai,Zhiyong Liang
出处
期刊:Cancer Letters
[Elsevier]
日期:2023-02-01
卷期号:555: 216040-216040
被引量:13
标识
DOI:10.1016/j.canlet.2022.216040
摘要
Pancreatic stellate cells (PSCs) are crucial for metabolism and disease progression in pancreatic ductal adenocarcinoma (PDAC). However, detailed mechanisms of PSCs in glutamine (Gln) metabolism and tumor-stromal metabolic interactions have not been well clarified. Here we showed that tumor tissues displayed Gln deficiency in orthotopic PDAC models. Single-cell RNA sequencing analysis revealed metabolic heterogeneity in PDAC, with significantly higher expression of Gln catabolism pathway in stromal cells. Significantly higher glutamine synthetase (GS) protein expression was further validated in human tissues and cells. Elevated GS levels in tumor and stroma were independently prognostic of poorer prognosis in PDAC patients. Gln secreted by PSCs increased basal oxygen consumption rate in PCCs. Depletion of GS in PSCs significantly decreased PCCs proliferation in vitro and in vivo. Mechanistically, activation of Wnt signaling induced directly binding of β-catenin/TCF7 complex to GS promoter region and upregulated GS expression. Rescue experiments testified that GS overexpression recovered β-catenin knockdown-mediated function on Gln synthesis and tumor-promoting ability of PSCs. Overall, these findings identify the Wnt/β-catenin/TCF7/GS-mediated growth-promoting effect of PSCs and provide new insights into stromal Gln metabolism, which may offer novel therapeutic strategies for PDAC.
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