Cell adhesion receptors play a critical role in tumor progression and metastasis. While in normal epithelial tissues cells are tightly adhere, cells in high-grade tumors are only loosely attached to each other, with cells at the tumor periphery displaying prominent loss of cell-cell adhesion and local tissue invasion. Decreased intercellular adhesion in high-grade tumors is often caused by a decreased expression or a complete loss of important cell-cell adhesion proteins. E-cadherin is clearly the best-studied example of such a protein and we have extensive knowledge concerning the mechanisms and the role of E-cadherin in tumor progression and metastasis. Our laboratory has being focused on understanding the role and significance of alpha-catenin, a cell-cell adhesion protein that links cadherin and catenins at the cell membrane with the actin cytoskeleton. Alpha-catenin is often lost or down regulated in high-grade epithelial tumors and loss of alpha-catenin correlates with metastatic progression and poor patient prognosis. We have recently demonstrated that alpha-catenin has an important tumor-suppressor function in Squamous Cell Carcinoma. The analysis of potential molecular mechanisms revealed a prominent connection between alpha-catenin and the Hippo signal transduction pathway. We present preliminary evidence demonstrating an important role of alpha-catenin in regulation of normal homeostasis of epidermal stem cells. We also show that the principal signaling function of alpha-catenin involves regulation of the activit of Src-family tyrosine kinases. In this grant application we propose to investigate the role of alpha-catenin in formation of cancer initiating cells in Squamous Cell Carcinoma and analyze the mechanisms and significance of Src-family kinases in regulation of Hippo signal transduction pathway, tumor initiation and progression.
Studies described in this project will help to understand the molecular mechanisms responsible for tumor progression. This knowledge is necessary for the future development of effective targeted therapeutic interventions in clinical oncology.