Study for Regulatory Mechanism of Dysadherin on Colorectal Cancer Progression

Abstract

Colorectal cancer (CRC) is one of the most devastating diseases with high mortality rate in the world and its progression and metastasis is the biggest challenges in treatment. The process of CRC progression is influenced by intracellular oncogenic mutations as well as the rearrangement of tumor microenvironment (TME) components including stromal cells and noncellular components like extracellular matrix (ECM). The activation of oncogenic signaling and interaction between cancer cells and TME permits cancer cells to acquire malignant phenotypes, spreading to distant sites from the primary site via a complex metastatic cascade. Therefore, comprehensive understanding of the molecular mechanism of malignant phenotype acquisition is still a requisite for providing therapeutic strategies for advanced CRC patients. Dysadherin is a cancer-associated antigen and cell membrane glycoprotein, which is found in multiple types of cancer cells, and has been identified as a strong inducer of tumor malignancy. However, the fundamental molecular mechanism by which dysadherin drives aggressive phenotype of cancer is not yet fully determined. Herein, I demonstrated the underlying mechanisms of dysadherin in multifaceted aspects. In part Ⅰ, I proposed that dysadherin is a key driver of mechanotransduction that contributes to CRC development and accelerates progression to the malignant phenotype. Empirically, the extracellular domain of dysadherin bound fibronectin and enhanced cancer cell adhesion to fibronectin, facilitating the activation of integrin-mediated mechanotransduction and leading to yes-associated protein 1 activation. Dysadherin-fibronectin interaction promoted cancer cell growth, survival, migration, and invasion, effects collectively mediated the protumor activity of dysadherin. In part Ⅱ, I found the intrinsic role of dysadherin in cell migration and invasion of colon cancer (CC). Comprehensive analysis revealed that aberrant cell migration and invasion resulted from impaired actin dynamics, focal adhesion turnover and protrusive structure formation upon dysadherin expression. Mechanistically, dysadherin activates FAK, leading to enhanced cell migration and invasion through the FAK/Rho GTPase cascade. In part Ⅲ, I revealed the extrinsic role of dysadherin in tumor progression and metastasis. I identified the matrix metalloprotease 9 (MMP9) as downstream target of dysadherin, contributing to initiating ECM remodeling within the TME and amplifying cancer progression. The dysadherin/MMP9 axis not only enhanced CRC cell invasiveness and ECM proteolytic activity but also activated cancer-associated fibroblasts, orchestrating the restructuring of the ECM through the synthesis of its components. Notably, dysadherin/MMP9 axis-induced ECM reorganization shaped immuno-suppressive and proangiogenic milieu. Collectively, these studies demonstrated that dysadherin has a pivotal role in promoting CRC development and accelerating progression to the malignant phenotype, paving the way for new molecular and biological insights as well as providing a basis for further development of new therapeutic strategies to overcome CRC progression.