Disrupting AGR2/IGF1 Paracrine and Reciprocal Signaling for Pancreatic Cancer Therapy

Overview

Journal Cell Rep Med

Publisher Cell Press

Date 2025 Feb 6

PMID 39914384

Authors

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

Jorg Kleeff

Helmut Friess

Maximilian Reichert

Zahra Dantes

Xiaoping Zou

Christoph W Michalski

Shanshan Shen

Bo Kong

Affiliations

Soon will be listed here.

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.

References

Ko A, LoConte N, Tempero M, Walker E, Kelley R, Lewis S . A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma. Pancreas. 2015; 45(3):370-5. PMC: 5908466. DOI: 10.1097/MPA.0000000000000458. View

Tsuji T, Satoyoshi R, Aiba N, Kubo T, Yanagihara K, Maeda D . Agr2 mediates paracrine effects on stromal fibroblasts that promote invasion by gastric signet-ring carcinoma cells. Cancer Res. 2014; 75(2):356-66. DOI: 10.1158/0008-5472.CAN-14-1693. View

Olive K, Jacobetz M, Davidson C, Gopinathan A, McIntyre D, Honess D . Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009; 324(5933):1457-61. PMC: 2998180. DOI: 10.1126/science.1171362. View

Kong B, Wu W, Cheng T, Schlitter A, Qian C, Bruns P . A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling. Gut. 2015; 65(4):647-57. DOI: 10.1136/gutjnl-2014-307616. View

Tiemann K, Garri C, Lee S, Malihi P, Park M, Alvarez R . Loss of ER retention motif of AGR2 can impact mTORC signaling and promote cancer metastasis. Oncogene. 2018; 38(16):3003-3018. PMC: 7523706. DOI: 10.1038/s41388-018-0638-9. View

Merugu S, Zhou B, Mangukiya H, Negi H, Ghulam R, Roy D . Extracellular AGR2 activates neighboring fibroblasts through endocytosis and direct binding to β-catenin that requires AGR2 dimerization and adhesion domains. Biochem Biophys Res Commun. 2021; 573:86-92. DOI: 10.1016/j.bbrc.2021.08.028. View

Cloots E, Guilbert P, Provost M, Neidhardt L, Van de Velde E, Fayazpour F . Activation of goblet-cell stress sensor IRE1β is controlled by the mucin chaperone AGR2. EMBO J. 2024; 43(5):695-718. PMC: 10907643. DOI: 10.1038/s44318-023-00015-y. View

Huang H, Wang Z, Zhang Y, Pradhan R, Ganguly D, Chandra R . Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer. Cancer Cell. 2022; 40(6):656-673.e7. PMC: 9197998. DOI: 10.1016/j.ccell.2022.04.011. View

Bachem M, Schunemann M, Ramadani M, Siech M, Beger H, Buck A . Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology. 2005; 128(4):907-21. DOI: 10.1053/j.gastro.2004.12.036. View

10.

Hoyne P, Elleman T, Adams T, Richards K, Ward C . Properties of an insulin receptor with an IGF-1 receptor loop exchange in the cysteine-rich region. FEBS Lett. 2000; 469(1):57-60. DOI: 10.1016/s0014-5793(00)01237-0. View

11.

Peng J, Sun B, Chen C, Zhou J, Chen Y, Chen H . Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 2019; 29(9):725-738. PMC: 6796938. DOI: 10.1038/s41422-019-0195-y. View

12.

Steele N, Carpenter E, Kemp S, Sirihorachai V, The S, Delrosario L . Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer. Nat Cancer. 2021; 1(11):1097-1112. PMC: 8294470. DOI: 10.1038/s43018-020-00121-4. View

13.

Li J, Stanger B . The tumor as organizer model. Science. 2019; 363(6431):1038-1039. DOI: 10.1126/science.aau9861. View

14.

Zhu Q, Mangukiya H, Saidi Mashausi D, Guo H, Negi H, Merugu S . Anterior gradient 2 is induced in cutaneous wound and promotes wound healing through its adhesion domain. FEBS J. 2017; 284(17):2856-2869. DOI: 10.1111/febs.14155. View

15.

Dumartin L, Alrawashdeh W, Trabulo S, Radon T, Steiger K, Feakins R . ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation. Oncogene. 2016; 36(22):3094-3103. PMC: 5467015. DOI: 10.1038/onc.2016.459. View

16.

Biffi G, Oni T, Spielman B, Hao Y, Elyada E, Park Y . IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer Discov. 2018; 9(2):282-301. PMC: 6368881. DOI: 10.1158/2159-8290.CD-18-0710. View

17.

Fuchs C, Azevedo S, Okusaka T, Van Laethem J, Lipton L, Riess H . A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015; 26(5):921-927. PMC: 4804122. DOI: 10.1093/annonc/mdv027. View

18.

Maurel M, Obacz J, Avril T, Ding Y, Papadodima O, Treton X . Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation. EMBO Mol Med. 2019; 11(6). PMC: 6554669. DOI: 10.15252/emmm.201810120. View

19.

Chen Y, Kim J, Yang S, Wang H, Wu C, Sugimoto H . Type I collagen deletion in αSMA myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer. Cancer Cell. 2021; 39(4):548-565.e6. PMC: 8423173. DOI: 10.1016/j.ccell.2021.02.007. View

20.

Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida A, Ponz-Sarvise M . Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017; 214(3):579-596. PMC: 5339682. DOI: 10.1084/jem.20162024. View