Patients with oral cavity cancers are treated with surgery, chemo and radiation therapy. Even with this aggressive treatment, only 40 to 50 percent of patients survive beyond 5 years, indicating a dire need for improved therapies. We also need ways to predict which patients will do well, so they can be spared toxicities, versus those who have a poor prognosis and should be treated more aggressively. Recent work suggests that there is a distinct population of cells within tumours that initiate and sustain tumour growth. Such tumour initiating cells (TICs) may be responsible for therapy-resistance. In addition to cancer cells, tumours contain normal cells from the body called stromal cells. We believe that the TICs use stromal cells the way a seed uses the soil. It is possible that by blocking the nutrients the stromal cells provide to the TICs, we may be able to interfere with cancer growth. This new avenue of research has yet to be translated into improved outcomes for patients. It is a major objective to demonstrate that knowledge of TICs and stromal cells will lead to improved diagnosis, prediction of responses, and superior treatments. This application has two major goals: 1) to understand the biology of TICs and stromal cells so we can develop ways to kill them; and 2) to determine whether the presence of TIC-related attributes is predictive of prognosis. We will separate out the TICs, stromal cells and other cell types in the tumour and determine what genes each is expressing. This will help us to understand how the TICs give rise to tumours and survive therapy, as well as how stromal cells support TICs, allowing us to develop new strategies to eliminate TICs, stromal cells, or both. We will also interrogate a number of TIC-related attributes to determine if any of them can provide a clinically useful test to determine which patients may benefit from more aggressive therapy, and which may be spared the toxicities of the current treatment protocols.