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광주과학기술원

Nat. Commun., Nov 30 2024, 15 (1) 10422 | https://doi.org/10.1038/s41467-024-54920-9 The dysadherin/MMP9 axis modifies the extracellular matrix to accelerate colorectal cancer progression

Choong-Jae Lee , Tae-Young Jang , So-El Jeon , Hyeon-Ji Yun , Yeong-Hoon Cho, Da-Ye Lim & Jeong-Seok Nam

School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.

Corresponding author
Correspondence to Jeong-Seok Nam.

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.

논문정보

형식Research article
게재일2024년 11월 (BRIC 등록일 2024-12-02)
연구진국내 연구진
분야 생명과학 > 노화/암생물학

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