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Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix

Author

Listed:
  • A. E. Yuzhalin

    (University of Oxford)

  • A. N. Gordon-Weeks

    (University of Oxford, John Radcliffe Hospital)

  • M. L. Tognoli

    (University of Oxford)

  • K. Jones

    (University of Oxford)

  • B. Markelc

    (University of Oxford)

  • R. Konietzny

    (University of Oxford)

  • R. Fischer

    (University of Oxford)

  • A. Muth

    (University of Massachusetts Medical School)

  • E. O’Neill

    (University of Oxford)

  • P. R. Thompson

    (University of Massachusetts Medical School)

  • P. J. Venables

    (Rheumatology and Musculoskeletal Sciences, University of Oxford)

  • B. M. Kessler

    (University of Oxford)

  • S. Y. Lim

    (University of Oxford
    Macquarie University)

  • R. J. Muschel

    (University of Oxford)

Abstract

Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis.

Suggested Citation

  • A. E. Yuzhalin & A. N. Gordon-Weeks & M. L. Tognoli & K. Jones & B. Markelc & R. Konietzny & R. Fischer & A. Muth & E. O’Neill & P. R. Thompson & P. J. Venables & B. M. Kessler & S. Y. Lim & R. J. Mus, 2018. "Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07306-7
    DOI: 10.1038/s41467-018-07306-7
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    Cited by:

    1. Shu Zhang & Wen Fang & Siqi Zhou & Dongming Zhu & Ruidong Chen & Xin Gao & Zhuojin Li & Yao Fu & Yixuan Zhang & Fa Yang & Jing Zhao & Hao Wu & Pin Wang & Yonghua Shen & Shanshan Shen & Guifang Xu & Le, 2023. "Single cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Rui Chen & Zhiyuan Lin & Shengqi Shen & Chuxu Zhu & Kai Yan & Caixia Suo & Rui Liu & Haoran Wei & Li Gao & Kaixiang Fan & Huafeng Zhang & Linchong Sun & Ping Gao, 2024. "Citrullination modulation stabilizes HIF-1α to promote tumour progression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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