Dysadherin Enhances Cancer Cell Motility by Changing Cell Mechanics

Abstract

Rationale: Dysadherin is a cancer-associated cell membrane glycoprotein enriched in various cancer cells including colorectal cancer (CRC), and its prominent expression in metastatic cancer is widely acknowledged. However, the fundamental role and mechanism of dysadherin in regulating single cell motility, its intermediate molecular mechanism is not yet fully understood. Methods: To get mechanistic insight, we explored to understand how dysadherin modulated single cell motility in terms of cytoskeleton dynamics. Then, ability of dysadherin that regulate persistent cell motility was verified after modifying expression of dysadherin or targeting motility-regulating cascade by dysadherin. Results: Aberrant cell motility via impaired actin dynamics, focal adhesion turnover and protrusive structure formation were observed upon the expression status of dysadherin. Furthermore, dysadherin-enriched cells have an increased focal adhesion kinase (FAK) cascade. In accordance with the incidental molecular properties induced by dysadherin deficiency, inhibiting FAK kinase activity efficiently amended mechanical and molecular impairment. Additionally, we developed a peptide-based inhibitor that inhibits the role of dysadherin in a cancer cell and verified that the inhibitor amended cell motility and viability. Conclusion: Our results highlight the role of dysadherin in modulating cancer cell motility via FAK signaling and also demonstrate that potential novel peptide-based inhibitor could restrain it.