Breast tumors are often identified based on their apparent hardness compared to normal breast tissue, and in breast cancer patients an increase in tissue rigidity is often correlated with an increase in metastasis. When human mammary epithelial cells are grown in 3D culture with the matrix stiffness of breast tumors, they develop a more malignant phenotype. The link between increased tissue rigidity and invasion and metastasis at the molecular level is not well understood. Previous research from the Yang lab has shown that the transcription factor Twist1 is a key regulator of metastasis through its ability to induce Epithelial-Mesenchymal Transition (EMT), a developmental program also used by cancer cells to invade and metastasize. The Yang lab discovered that upon an increase in matrix stiffness, Twist1 translocates from the cytoplasm into the nucleus. Under low matrix stiffness, Twist1 is bound to its cytoplasmic anchor GTPase activating protein binding protein 2 (G3BP2). This interaction is controlled by phosphorylation of tyrosine 107 on Twist1 (Y107), which in turn releases Twist1 from G3BP2 to enter the nucleus. Initial studies to identify the kinase responsible for this phosphorylation event identified a tyrosine kinase that caused Twist1 nuclear accumulation at low matrix stiffness, suggesting that this candidate kinase is required for cytoplasmic localization of Twist1 at low stiffness. Therefore, I hypothesize that this candidate kinase controls Twist1 subcellular localization in response to changes in matrix stiffness via the Twist1 mechanoregulation pathway. To test this hypothesis I plan to 1-2) Determine the role that this candidate plays in this mechanotransduction pathway; 3) determine the role of this candidate kinase in Twist1 dependent invasion and metastasis in vivo.
The proposed research aims to determine how mechanical forces are translated into biochemical signals to promote tumor invasion and metastasis. We believe that our work to understand the molecular mechanism of this mechanotransduction pathway will uncover a novel tumor invasion regulatory pathway, and will provide new targets for anti-metastasis therapy.
