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The dysadherin/MMP9 axis modifies the extracellular matrix to accelerate colorectal cancer progression

Author

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  • Choong-Jae Lee

    (Gwangju Institute of Science and Technology)

  • Tae-Young Jang

    (Gwangju Institute of Science and Technology)

  • So-El Jeon

    (Gwangju Institute of Science and Technology)

  • Hyeon-Ji Yun

    (Gwangju Institute of Science and Technology)

  • Yeong-Hoon Cho

    (Gwangju Institute of Science and Technology)

  • Da-Ye Lim

    (Gwangju Institute of Science and Technology)

  • Jeong-Seok Nam

    (Gwangju Institute of Science and Technology)

Abstract

The dynamic alteration of the tumor microenvironment (TME) serves as a driving force behind the progression and metastasis of colorectal cancer (CRC). Within the intricate TME, a pivotal player is the extracellular matrix (ECM), where modifications in components, degradation, and stiffness are considered critical factors in tumor development. In this study, we find that the membrane glycoprotein dysadherin directly targets matrix metalloprotease 9 (MMP9), initiating ECM remodeling within the TME and amplifying cancer progression. Mechanistically, the dysadherin/MMP9 axis not only enhances CRC cell invasiveness and ECM proteolytic activity but also activates cancer-associated fibroblasts, orchestrating the restructuring of the ECM through the synthesis of its components in human CRC cells, patient samples, and mouse models. Notably, disruption of ECM reorganization by dysadherin knockout results in a discernible reduction in the immunosuppressive and proangiogenic milieu in a humanized mouse model. Intriguingly, these effects are reversed upon the overexpression of MMP9, highlighting the intricate and pivotal role of the dysadherin/MMP9 axis in shaping the development of a malignant TME. Therefore, our findings not only highlight that dysadherin contributes to CRC progression by influencing the TME through ECM remodeling but also suggest that dysadherin may be a potential therapeutic target for CRC.

Suggested Citation

  • Choong-Jae Lee & Tae-Young Jang & So-El Jeon & Hyeon-Ji Yun & Yeong-Hoon Cho & Da-Ye Lim & Jeong-Seok Nam, 2024. "The dysadherin/MMP9 axis modifies the extracellular matrix to accelerate colorectal cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54920-9
    DOI: 10.1038/s41467-024-54920-9
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    References listed on IDEAS

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    1. Juliane Winkler & Abisola Abisoye-Ogunniyan & Kevin J. Metcalf & Zena Werb, 2020. "Concepts of extracellular matrix remodelling in tumour progression and metastasis," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    2. Janine T. Erler & Kevin L. Bennewith & Monica Nicolau & Nadja Dornhöfer & Christina Kong & Quynh-Thu Le & Jen-Tsan Ashley Chi & Stefanie S. Jeffrey & Amato J. Giaccia, 2006. "Lysyl oxidase is essential for hypoxia-induced metastasis," Nature, Nature, vol. 440(7088), pages 1222-1226, April.
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