Objective Pancreatic 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.
Design Two 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.
Results IL-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.
Conclusions Our 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.
- pancreatic cancer
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Contributors YC generated the ideas and designed experiments. XS and YY performed most experiments and organised all figures. XH, YZ, KH, PA, JingW, JieyuW, XJ, QD and XH participated in experimentation. RB, BD, ZG, AH and XL provided important materials and reagents. YW, QJ, YY and QL participated in discussions. YC wrote the manuscript.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval All animal studies were approved by the North Stockholm Animal Ethical Committee, Stockholm, Sweden or by the Animal Experimental Ethical Committee of the Fudan University, Shanghai, China. All human PDAC studies were approved by the Ethical Review Committee in the Shuguang Hospital, the Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Pancreatic tumour samples and adjacent pancreatic tissues were collected from patients with cancer with written permission.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available in a public, open access repository. Gene array and RNA-seq data are freely accessible in the public repository Gene Expression Omnibus under the links: gene expression profile of F4/80+ cells isolated from tumours implanted in wild type and St2−/− mouse: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE69402. Gene expression profile of RAW264.7 monocytes treated with or without IL-33: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE97657 RNA-seq data of primary mouse fibroblast treated with or without CXCL3: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166263. Other data are available upon reasonable request.
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