ABSTRACT/ PROJECT SUMMARY Invasion is required for development and spread of head and neck cancer (HNC) but unfortunately there are no strategies that effectively target invasion. This knowledge gap is due to limited progress in identifying and understanding the underlying mechanisms that control invasion. While progress has been made in establishing that epithelial to mesenchymal transition in HNC cells allows them to spread and become resistant to treatment, critical mechanistic links are unknown. It is also unclear which tumors will spread and become resistant to treatment. Given the continued poor survival of patients with HNC, this project will address the following questions: 1) what are the mechanisms that encourage HNC to spread; 2) how is HNC protected from radiation and who is at risk for developing resistance; and 3) how does HNC recur. This work will provide the foundation for novel mechanism-based treatment strategies to improve the survival of patients with HNC.