The overall objective of this project is the generation of inducible mouse models that closely mimic the development of human skin and head and neck cancers. My colleagues and I have recently developed inducible mouse models that allow the activation of oncogenes or inactivation of tumor suppressor genes in a restricted area of the skin, oral cavity or esophagus in stem cells that renew these stratified epithelia. Thus, we can create mice with discrete genetic changes in somatic cells that are identical to events that are thought to occur in human tumors. The genetic changes identified to date are primarily associated with early stages of tumor development. Much less is known about genetic changes that occur as tumors progress to metastatic lesions. Thus, our application will focus on recently discovered candidate genes implicated in promoting tumor progression through mechanisms that are both dependent on and independent of genomic instability. To identify novel genetic changes associated with tumor progression in our inducible mouse models, we will analyze tumors using both Affymetrix arrays and BAC/CGH arrays. In parallel studies, we will also analyze human skin and head and neck tumors which exhibit an aggressive nature and propensity to metastasize by Affymetrix arrays and BAC/CGH arrays and compare these findings with results obtained from analysis of the mouse tumors. Our inducible mouse models develop tumors as the result of discrete genetic changes, therefore these models are ideally suited to test novel drugs designed to interfere with specific gene products or signaling pathways. Pilot experiments will be performed to assess the utility of these models as tools for translational studies. Imaging will be utilized for the early detection of metastatic lesions in these studies and to monitor regression following treatment.
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