Extracellular Matrix Topology Regulates Tumor Cell Migration Via Cav-1/YAP Mechanotransduction

The major cause of cancer death is tumor metastasis.In the metastasis process of breast cancer,the arrangement of collagen fibers has obvious changes in different stages of tumor development,which provides a path for tumor cell migration.Caveolin-1（Cav-1）plays an important role in responding to mechanical signals.It converts extracellular mechanical signals into chemical signals through a series of mechanotransduction processes to regulate the cell biological behaviors.Cell migration requires driving force,the dynamic equilibrium between focal adhesions and cytoskeleton polymerization is the main driving force driving cells to move forward.Known as "mechanical switch",YAP has been proved to participate in the response of various mechanical signals,which regulates its target genes expression through its transcriptional function,thus regulates the survival,proliferation,migration and invasion of tumor cells.Although many studies have focused on how extracellular matrix mechanics regulate cell behavior and molecular mechanisms involved,it is not clear how altered fiber arrangement affects cell migration in the progression of breast cancer.Therefore,the purpose of this thesis is to study the molecular mechanism of the regulation of the migration of MDA-MB-231 cells in three negative breast cancer cells by different arrangement of extracellular fibers,so as to provide innovative thoughts and strategies for the treatment and prevention of tumors.In the thesis,high invasive breast cancer cell line MDA-MB-231 was used as the research object,and electrospinning technology was used to construct random / aligned fibers to explore the behavior differences of tumor cells in random / aligned fibers.It is found that the cells present a slender phenotype consistent along the fiber direction on aligned fibers,and the cytoskeleton is not only an important molecule determining the cell morphology,but also an important participant in regulating the cell migration.Therefore,it is further explored that the migration ability of cells on the two kinds of fibers is different,and it is found that cells show the strongest migration ability on aligned fibers.The difference in the expression of Cav-1 was observed on two different fibers,which led us to assume that cell migration was mediated by Cav-1 in response to extracellular mechanical signals.As expected,aligned fibers can promote cell migration by promoting the expression of Cav-1,regulating the distribution of integrin and enhancing the growth of focal adhesions.The nuclear localization of YAP was also regulated by Cav-1,and the strongest nuclear localization of YAP was observed in sh Con cells on aligned fibers.Subsequent studies confirmed that YAP with transcriptional activity regulates the polymerization of cytoskeleton actin and the formation of focal adhesions at the transcriptional level,and then participates in the regulation of continuous cell migration.In conclusion,this study found that aligned fibers can enhance the formation of focal adhesions and the polymerization of actin by promoting the expression of Cav-1,so as to regulate the transcriptional activity of YAP and cell migration.In order to prevent cells from over anchoring the matrix,activated YAP in turn regulates the focal adhesions formation and actin polymerization at the transcriptional level,so as to achieve a dynamic balance between focal adhedion dynamics and cytoskeleton polymerization during cell migration,so as to regulate the continuous migration of cells.