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Disrupting AGR2/IGF1 paracrine and reciprocal signaling for pancreatic cancer therapy

Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and characterized by pronounced desmoplasia. PDAC cells communicate with cancer-associated fibroblasts (CAFs) in a paracrine/reciprocal manner, substantially promoting tumor growth and desmoplastic responses. This study highlights the crit...

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Main Authors: Li, Hongzhen (Author) , Zhang, Zhiheng (Author) , Shi, Zhao (Author) , Zhou, Siqi (Author) , Nie, Shuang (Author) , Yu, Yuanyuan (Author) , Zhang, Lingling (Author) , Sun, Yifeng (Author) , Fang, Chao (Author) , Hu, Jingxiong (Author) , Niu, Yiqi (Author) , Schuck, Kathleen (Author) , Wang, Lei (Author) , Jiang, Kuirong (Author) , Lu, Zipeng (Author) , Kahlert, Christoph (Author) , Roth, Susanne (Author) , Loos, Martin (Author) , Herr, Ingrid (Author) , Sunami, Yoshiaki (Author) , Kleeff, Jörg H. (Author) , Friess, Helmut (Author) , Reichert, Maximilian (Author) , Dantes, Zahra (Author) , Zou, Xiaoping (Author) , Michalski, Christoph (Author) , Shen, Shanshan (Author) , Kong, Bo (Author)
Format: Article (Journal)
Language:English
Published: 18 February 2025
In: Cell reports. Medicine
Year: 2025, Volume: 6, Issue: 2, Pages: 1-25
ISSN:2666-3791
DOI:10.1016/j.xcrm.2024.101927
Online Access:Resolving-System, kostenfrei: https://doi.org/10.1016/j.xcrm.2024.101927
Resolving-System, kostenfrei: https://doi.org/10.25673/118733
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2666379124006980
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Author Notes:Hongzhen Li, Zhiheng Zhang, Zhao Shi, Siqi Zhou, Shuang Nie, Yuanyuan Yu, Lingling Zhang, Yifeng Sun, Chao Fang, Jingxiong Hu, Yiqi Niu, Kathleen Schuck, Lei Wang, Kuirong Jiang, Zipeng Lu, Christoph Kahlert, Susanne Roth, Martin Loos, Ingrid Herr, Yoshiaki Sunami, Jörg Kleeff, Helmut Friess, Maximilian Reichert, Zahra Dantes, Xiaoping Zou, Christoph W. Michalski, Shanshan Shen, and Bo Kong
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Summary:Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and characterized by pronounced desmoplasia. PDAC cells communicate with cancer-associated fibroblasts (CAFs) in a paracrine/reciprocal manner, substantially promoting tumor growth and desmoplastic responses. This study highlights the critical role of anterior gradient 2 (AGR2), an endoplasmic reticulum protein disulfide isomerase, secreted by PDAC cells to activate CAFs via the Wnt signaling pathway. Activated CAFs, in turn, secrete insulin-like growth factor 1 (IGF1), which enhances AGR2 expression and secretion in PDAC cells through the IGF1 receptor (IGF1R)/c-JUN axis. Within PDAC cells, AGR2 acts as a thioredoxin, aiding the folding and cell surface presentation of IGF1R, essential for PDAC’s response to CAF-derived IGF1. This reciprocal AGR2/IGF1 signaling loop intensifies desmoplasia, immunosuppression, and tumorigenesis, creating a harmful feedback loop. Targeting both pathways disrupts this interaction, reduces desmoplasia, and restores anti-tumor immunity in preclinical models, offering a promising therapeutic strategy against PDAC.
Item Description:Online verfügbar 5 February 2025, Version des Artikels 18 February 2025
Gesehen am 29.07.2025
Physical Description:Online Resource
ISSN:2666-3791
DOI:10.1016/j.xcrm.2024.101927

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