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 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.
Authors
- Kathleen Schuck (ORCID: https://orcid.org/0009-0003-2769-046X)
- Jörg Kleeff (ORCID: https://orcid.org/0000-0003-3432-6669)
- Jingxiong Hu
- Zipeng Lu
- Lingling Zhang (ORCID: https://orcid.org/0000-0001-5070-8523)
- Shanshan Shen (ORCID: https://orcid.org/0000-0003-3249-1564)
- Susanne Roth (ORCID: https://orcid.org/0000-0002-5136-4686)
- Lei Wang (ORCID: https://orcid.org/0000-0001-7275-4846)
- Christoph Kahlert (ORCID: https://orcid.org/0000-0003-4124-7918)
- Yoshiaki Sunami (ORCID: https://orcid.org/0000-0002-1235-7512)
- Maximilian Reichert (ORCID: https://orcid.org/0000-0002-8611-5639)
- Zahra Dantes (ORCID: https://orcid.org/0000-0002-4625-2524)
- Christoph Michalski (ORCID: https://orcid.org/0000-0003-3520-1040)
- Ingrid Herr (ORCID: https://orcid.org/0000-0002-2389-6300)
- Zhiheng Zhang (ORCID: https://orcid.org/0000-0003-4299-5379)
- Yuanyuan Yu (ORCID: https://orcid.org/0000-0001-7945-6833)
- Hongzhen Li (ORCID: https://orcid.org/0000-0001-6393-3009)
- Yifeng Sun (ORCID: https://orcid.org/0000-0001-7561-9367)
- Yanan Niu (ORCID: https://orcid.org/0009-0007-8662-3696)
- Kuirong Jiang (ORCID: https://orcid.org/0000-0001-9512-6463)
- Chao Fang (ORCID: https://orcid.org/0000-0003-0005-6939)
- Helmut Frieß
- Shuang Nie
- Xiaoping Zou
- Zhao Shi
- Siqi Zhou (ORCID: https://orcid.org/0009-0000-5436-1256)
- Martin Loos
Institutions
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- TUM Klinikum (DE)
- Nanjing Drum Tower Hospital (CN)
- Jiangsu Province Hospital (CN)
- University Hospital Ulm (DE)
- Technical University of Munich (DE)
- Martin Luther University Halle-Wittenberg (DE)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101927
- Citations
- 10
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 10.45