Dysadherin/MMP9 axis Promotes Colorectal Cancer Metastasis via ECM Remodeling

Abstract

Dysadherin is a cancer-associated cell membrane glycoprotein which is identified as a strong inducer of colorectal cancer (CRC) cell invasion and metastasis. However, its underlying mechanism is not entirely understood. Here, we performed the comprehensive bioinformatics analysis using dysadherin knockout CRC cell and clinical genomic database of CRC. Mechanistically, we identified that the effect of dysadherin deletion is linked to a reduction of extracellular matrix (ECM) remodeling via reducing expression of matrix metalloprotease 9 (MMP9). Consistent with the discovered mechanism, knockout of dysadherin impaired MMP9 activation, ECM degradation and tumor invasiveness in human CRC cells, patient samples and mouse models for CRC metastasis. Furthermore, we verified that dysadherin/MMP9 axis regulated tumor microenvironment such as angiogenesis by promoting ECM remodeling in mouse model of CRC metastasis. Thus, our results highlight a novel function of dysadherin as a driver of invasion and metastasis via MMP9-mediated ECM remodeling, providing a potential therapy strategy for CRC metastasis.