Disrupting AGR2/IGF1 paracrine and reciprocal signaling for pancreatic cancer therapy
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 Michalski, Shanshan Shen, Bo Kong
Abstract
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. • Targeting AGR2/IGF1 disrupts harmful signaling in pancreatic cancer • AGR2 and IGF1R co-inhibition reduces desmoplasia and immunosuppression • Combined therapy restores anti-tumor immunity in preclinical PDAC models • AGR2/IGF1 loop promotes PDAC progression via CAF activation and IGF1 secretion PDAC interacts with stromal cells through secreted factors. Li et al. find that AGR2 secreted from tumor cells acts on CAFs to stimulate IGF1 secretion, which promotes the progression of PDAC. Targeting the AGR2/IGF1 loop restores anti-tumor immunity in PDAC, possessing potential therapeutic significance.