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Original research
Inflammatory cell-derived CXCL3 promotes pancreatic cancer metastasis through a novel myofibroblast-hijacked cancer escape mechanism
  1. Xiaoting Sun1,2,3,
  2. Xingkang He2,
  3. Yin Zhang2,
  4. Kayoko Hosaka2,
  5. Patrik Andersson2,
  6. Jing Wu2,
  7. Jieyu Wu2,
  8. Xu Jing2,
  9. Qiqiao Du2,
  10. Xiaoli Hui4,
  11. Bo Ding5,
  12. Ziheng Guo6,
  13. An Hong7,
  14. Xuan Liu8,
  15. Yan Wang1,3,
  16. Qing Ji1,3,
  17. Rudi Beyaert9,
  18. Yunlong Yang10,
  19. Qi Li1,3,
  20. Yihai Cao2
  1. 1Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
  2. 2Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institutet, Stockholm, Sweden
  3. 3Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
  4. 4Department of Geriatric-Endocrinology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
  5. 5Department of Respiratory Disease, The Fourth Hospital of Jinan, Jinan, China
  6. 6Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
  7. 7Institute of Biomedicine & Department of Cell Biology, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
  8. 8Changzheng Hospital, Second Military Medical University, Shanghai, China
  9. 9VIB-UGent Center for Inflammation Research, VIB; Department of Biomedical Molecular Biology, Ghent University, Belgium
  10. 10Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
  1. Correspondence to Dr. Yunlong Yang, Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China; yunlongyang{at}fudan.edu.cn; Dr. Qi Li, Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; qili{at}shutcm.edu.cn; Dr. Yihai Cao, Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institutet, Stockholm, Sweden; yihai.cao{at}ki.se

Abstract

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
  • myofibroblasts
  • macrophages
  • interleukins
  • chemokines

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Footnotes

  • 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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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