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

被引:2
|
作者
Lee, Choong-Jae [1 ]
Jang, Tae-Young [1 ]
Jeon, So-El [1 ]
Yun, Hyeon-Ji [1 ]
Cho, Yeong-Hoon [1 ]
Lim, Da-Ye [1 ]
Nam, Jeong-Seok [1 ]
机构
[1] Gwangju Inst Sci & Technol, Sch Life Sci, Gwangju 61005, South Korea
基金
新加坡国家研究基金会;
关键词
CELL-SURFACE; EXPRESSION; FIBROBLASTS; METASTASIS; GROWTH; PROMOTES; MMP-9; ANGIOGENESIS; ACTIVATION; MOTILITY;
D O I
10.1038/s41467-024-54920-9
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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. The extracellular matrix (ECM) is a key component of the tumor microenvironment (TME) in colorectal cancer (CRC). Here, the authors identify that the membrane glycoprotein dysadherin upregulates matrix metalloprotease 9 (MMP9) to induce ECM remodeling and subsequent activation of cancer-associated fibroblasts in TME to promote CRC metastasis.
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页数:14
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