Journal Article

Inflammatory cell-derived CXCL3 promotes pancreatic cancer metastasis through a novel myofibroblast-hijacked cancer escape mechanism

Sun, Xiaoting, Zhang, Yin, Hosaka, Kayoko, Hui, Xiaoli, Li, Qi, Ji, Qing, Guo, Ziheng, He, Xingkang, Wu, Jieyu, Ding, Bo, Wang, Yan, Wu, Jing, Yang, Yunlong, Liu, Xuan, Jing, Xu, Cao, Yihai, Du, Qiqiao, Beyaert, Rudi, Andersson, Patrik, Hong, An

2022

Overview

ObjectivePancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy and lacks effective treatment. We aimed to understand molecular mechanisms of the intertwined interactions between tumour stromal components in metastasis and to provide a new paradigm for PDAC therapy.DesignTwo unselected cohorts of 154 and 20 patients with PDAC were subjected to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain-of-function and loss-of-function approaches were employed to identify molecular signalling in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated fibroblasts (myoCAFs). The role of the IL-33–ST2–CXCL3–CXCR2 axis in PDAC metastasis was evaluated in three clinically relevant mouse PDAC models.ResultsIL-33 was specifically elevated in human PDACs and positively correlated with tumour inflammation in human patients with PDAC. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. Mechanistically, activation of the IL-33–ST2–MYC pathway attributed to high CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth muscle actin (α-SMA) was uniquely upregulated by the CXCL3–CXCR2 signalling. Type III collagen was identified as the CXCL3–CXCR2-targeted adhesive molecule responsible for myoCAF-driven PDAC metastasis.ConclusionsOur work provides novel mechanistic insights into understanding PDAC metastasis by the TAM-CAF interaction and targeting each of these signalling components would provide an attractive and new paradigm for treating pancreatic cancer.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD
• Subject: Actin / Adenocarcinoma / Animal models / Animals / Antibodies / Cancer-Associated Fibroblasts - metabolism / Carcinoma, Pancreatic Ductal - mortality / Carcinoma, Pancreatic Ductal - pathology / chemokines / Chemokines, CXC - metabolism / Cohort Studies / Collagen / Collagen (type III) / CXCR2 protein / Cytokines / Fibroblasts / Genomes / Growth factors / Humans / Inflammation / Interleukin-33 - metabolism / interleukins / Macrophages / Malignancy / Medical prognosis / Metastases / Metastasis / Mice / Mice, Knockout / Molecular modelling / Myc protein / myofibroblasts / Neoplasm Metastasis / Pancreas / Pancreatic cancer / Pancreatic Neoplasms - mortality / Pancreatic Neoplasms - pathology / Patients / Polymerase chain reaction / Proteins / Signal transduction / Smooth muscle / Tumor-Associated Macrophages - metabolism / Tumors / Up-Regulation