Pancreatic cancer is one of the leading causes of cancer-associated mortality. One of the primary contributing factors is late diagnosis of the disease, resulting in established metastatic cancer before symptoms emerge. This form of cancer is characterised by a number of well-defined genetic alterations including oncogenic mutation of K-Ras and inactivating mutation of p53, SMAD4 and CDKN2A. Concurrent deregulation of K-ras and these tumor suppressors facilitates uncontrolled proliferation of early stage pancreatic cancer cells and subsequent progression into more advanced adenocarcinomas. However, as many patients present with a metastatic form of pancreatic cancer, treatment of the primary tumor is often insufficient to achieve regression of this disease. Thus, a greater understanding of pancreatic cancer metastasis is needed to identify mechanisms to effectively treat this form of cancer. We wish to perform an in vivo shRNA screen to identify genes that promote or inhibit metastasis of oncogenic K-Ras positive pancreatic cancer cells. We will then investigate the mechanism through which these genes regulate the metastatic process. Finally, we will explore methods to modulate these genes and/or their function for the treatment of pancreatic cancer.
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