| Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a grave prognosis. Identification of single genetic mutations, such as mutant Kras, involved in the initiation and progression of this cancer has facilitated a greater understanding of its basic biology. However, fundamental questions about the cell of origin remain unanswered. Using the Ela-Kras mouse previously developed in the laboratory, I have shown that targeting mutant Kras to pancreatic acinar cells results in preinvasive ductal lesions with morphology similar to human pancreatic intraepithelial neoplasms (PanINs). Additional loss of the tumor suppressor genes p16 or p53 results in metastatic pancreatic ductal adenocarcinoma or acinar cell carcinomas. Both tumor types display similar biologic behavior as the human disease, including similar activation of signaling pathways implicated in human PDAC pathogenesis. Genetic analyses further distinguished the ductal or acinar cell tumors based on areas of chromosomal copy number gains/losses.The development of preinvasive ductal lesions and invasive metastatic PDAC makes Ela-Kras p16+/- mice a good model in which to test therapies. These mice were used in a chemotherapy trial to test the efficacy of 5-Fluorouracil on tumor growth based on monitoring of tumor volumes acquired by high resolution MRI. No effect of 5-FU on the primary tumor growth or metastatic potential was noted in these mice, but this study demonstrated the feasibility of clinical trials in these mice.To specifically address the potential of ductal epithelial cells as tumor-initiating cells in PDAC, I developed mouse models in which oncogene expression is restricted to pancreatic ductal epithelial cells. Mutant Kras or overexpressed ErbB2 was targeted to ductal epithelial cells using a novel cre/lox recombination scheme, restricting oncogene expression to CK19 positive cells in the pancreas. There was no evidence of ductal dysplasia/preneoplasia noted in the Kras mice. The ErbB2 mice are being evaluated. |
