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Original research
Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment
  1. Zhibo Xie1,2,
  2. Ya Gao3,
  3. Chiakang Ho3,
  4. Lequn Li4,
  5. Chen Jin2,
  6. Xiaoyi Wang2,
  7. Caifeng Zou2,
  8. Yishen Mao2,
  9. Xiaobo Wang4,
  10. Qingfeng Li3,
  11. Deliang Fu2,
  12. Yi-Fan Zhang3
  1. 1Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Children's Hospital, Shanghai, China
  2. 2Department of Pancreatic Surgery, Huashan Hospital Fudan University, Shanghai, Shanghai, China
  3. 3Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, Shanghai, China
  4. 4Department of Hepatobiliary and Pancreas Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China
  1. Correspondence to Dr Yi-Fan Zhang, Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China; zhangyifan82{at}126.com; Professor Deliang Fu; lunwenfudan{at}163.com; Professor Qingfeng Li; dr.liqingfeng{at}shsmu.edu.cn

Abstract

Objective Pancreatic ductal adenocarcinoma (PDAC) shows a remarkable predilection for liver metastasis. Pro-oncogenic secretome delivery and trafficking via exosomes are crucial for pre-metastatic microenvironment formation and metastasis. This study aimed to explore the underlying mechanisms of how PDAC-derived exosomes (Pex) modulate the liver microenvironment and promote metastasis.

Design C57BL/6 mice were ‘educated’ by tail vein Pex injection. The intrasplenic injection liver metastasis and PDAC orthotopic transplantation models were used to evaluate liver metastasis. Stable cell lines CD44v6 (CD44 variant isoform 6) or C1QBP (complement C1q binding protein) knockdown or overexpression was established using lentivirus transfection or gateway systems. A total of 142 patients with PDAC in Huashan Hospital were retrospectively enrolled. Prognosis and liver metastasis were predicted using Kaplan-Meier survival curves and logistic regression models.

Results Pex tail vein injection induced the deposition of liver fibrotic extracellular matrix, which promoted PDAC liver metastasis. Specifically, the exosomal CD44v6/C1QBP complex was delivered to the plasma membrane of hepatic satellite cells (HSCs), leading to phosphorylation of insulin-like growth factor 1 signalling molecules, which resulted in HSC activation and liver fibrosis. Expression of Pex CD44v6 and C1QBP in PDAC patients with liver metastasis was significantly higher than in PDAC patients without liver metastasis, and simultaneous high expression of exosomal CD44v6 and C1QBP correlated with a worse prognosis and a higher risk of postoperative PDAC liver metastasis.

Conclusion The Pex-derived CD44v6/C1QBP complex is essential for the formation of a fibrotic liver microenvironment and PDAC liver metastasis. Highly expressed exosomal CD44v6 and C1QBP are promising biomarkers for predicting prognosis and liver metastasis in patients with PDAC.

  • pancreatic cancer
  • liver metastases
  • extracellular matrix
  • fibrosis
  • molecular oncology

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. All data supporting the findings of this study are available within the article and its Supplementary Information files. RNA-seq data have been deposited in Gene Expression Omnibus with the primary accession code GSE148139.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. All data supporting the findings of this study are available within the article and its Supplementary Information files. RNA-seq data have been deposited in Gene Expression Omnibus with the primary accession code GSE148139.

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Footnotes

  • ZX, YG and CH contributed equally.

  • Contributors Conceptualisation: Y-FZ, ZX, DF and QL. Methodology: ZX, YG, CH, Y-FZ, Xiaoyi Wang, Xiaobo Wang, CJ and LL. Investigation: ZX, YG, CH, Xiaobo Wang, CZ, LL and YM. Data curation and formal analysis: ZX, Xiaoyi Wang, YG, CH, Y-FZ and DF. Funding: Y-FZ, ZX and DF. Writing-original draft: ZX and Y-FZ. Review and editing: Y-FZ, DF, QL and CJ. Project administration and resources: Y-FZ., ZX, DF and QL. Supervision: Y-FZ, DF and QL. All authors read and approved the final manuscript.

  • Funding This study was supported by grants from National Natural Science Foundation of China (Grant No. 81902432 to ZX; Grant No. 81901963 to Y-FZ; Grant No. 81472221 to DF), Shanghai Sailing Program (Grant No. 19YF1426700 to Y-FZ), Shanghai 'Rising Stars of Medical Talent' Youth Development Program (Y-FZ), Young Physician Innovation Team Project of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (Grant No. QC202001 to Y-FZ) and Cross-disciplinary Research Fund of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (Grant No. JYJC201908 to Y-FZ).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • 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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