Dysadherin/MMP9 axis Promotes Colorectal Cancer Metastasis via ECM Remodeling

Abstract

Purpose: Metastasis is the main cause of cancer-related mortality and requires multiple cascade including invasion, intravasation, extravasation. Dysadherin is a cancer-associated cell membrane glycoprotein which is identified as a strong inducer of colorectal cancer (CRC) cell invasion and metastasis. However, the fundamental molecular mechanism by which dysadherin drives invasion and metastasis is not fully elucidated. Methods: To get a mechanistic insight, we performed bioinformatics analysis to identify downstream signaling of dysadherin using RNA sequencing profiles from dysadherin knockout CRC cell and clinical genomic database of CRC. Next, we explored the downstream event of dysadherin in human CRC cells, patient samples and mouse models for CRC metastasis. Results: The results of comprehensive bioinformatics analysis suggested that the effect of dysadherin deletion is linked to a reduction of extracellular matrix (ECM) remodeling that is essential for premetastatic niche formation. Mechanistically, we identified matrix metalloprotease 9 (MMP9) which enhanced the ECM degradation and premetastatic niche formation. Consistent with the discovered mechanism, knockout of dysadherin impaired MMP9 activation, ECM degradation and tumor invasiveness, reducing the aggressive behavior of CRC cells. Furthermore, we verified that dysadherin/MMP9 axis regulated tumor microenvironment such as angiogenesis by promoting ECM remodeling in CRC cells and mouse model of CRC metastasis. Conclusions: 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.