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Over the last thirty years, improvements in survival rates of oral cancer patients have remained modest, and have been hampered by the late detection of the disease and a lack of actionable targets. We recently established a novel concept for oral cancer development in mouse models that mirror the human disease. The novel concept will now allow us to address these issues and to identify predictive markers and cancer-initiating mechanisms. Findings from the current project will discover markers of disease initiation for early detection as well as therapeutic targets against this aggressive cancer.