Abstract 2384: A novel mouse model for the study of c-MYC during initiation and progression of pancreatic ductal adenocarcinoma
Authors: Lin Wan-Chi , Zhang Qian , Opavsky Rene , DiMaio Dominick J. , Felsher Dean W. , Batra Surinder K. , Hollingsworth Michael A. , Wagner Kay-Uwe 
Published: June 2012

Pancreatic cancer is one of the most deadly human malignant diseases. The median 5-year survival rate of patients is less than 5%. During the progression of precursor lesions into PDAC, somatic mutations within critical tumor susceptibility loci accumulate, including Kras, Cdkn2a, and Trp53. Also, overexpression of the c-Myc oncogene has been reported in a subset (i.e. between 30-40%) of primary PDACs and in more than half of pancreatic cancer cell lines. In addition to these published reports, we have analyzed the expression of the c-Myc oncoprotein within PanIN lesions as well as primary and metastatic PDACs and found this oncoprotein is already present in the earliest precursor lesions (PanINs). This finding indicates that upregulation of c-Myc is one of the earliest events in neoplastic transformation in the pancreas. Despite the significant role of c-Myc in the onset of human pancreatic cancer, this oncoprotein was found to be present only in a subset of primary PDACs and metastatic cases, implying that not all cases of human PDACs are “addicted” to this oncogene.

To experimentally address whether c-Myc is required for the survival of cancer cells in primary and metastatic lesions that express this transcription factor, we have developed a novel mouse model that allows a spatially and temporally controlled expression of genes in a ligand (tetracycline)-controlled manner. Transgenic mice expressing c-Myc in the pancreatic ductal epithelium developed malignancies within 6 months. The majority of these tumors (about 75%) are ductal lesions and about 25% are poorly differentiated cancers that lack expression of CK19 and might be of acinar origin. Ablation of c-Myc expression in PanIN lesions as well as primary pancreatic cancers results in cell death and tumor regression, suggesting that the proliferation and survival of neoplastic pancreatic cells depend on the expression of the transforming oncogene. Our recent observations also show that the expression of c-Myc itself is sufficient to cause primary tumors that sporadically metastasize to the liver. These metastatic lesions in the mouse exhibit similar histopathological features and CK19 expression comparable to human PDAC.

In summary, we have developed a novel mouse model in which c-Myc (and potentially other oncogenes) can be expressed in the pancreas of adult animals in a temporally and spatially controlled manner. Being able to regulate the expression of transforming oncogenes prior to and following neoplastic transformation, allows us to assess the continued significance of cancer initiating mutations at defined stages of the progressing disease. The in-depth characterization of this newly developed pancreatic cancer model will permit us to search for biomarkers that could be valuable to detect cancer shortly after disease initiation in vivo.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2384. doi:10.1158/1538-7445.AM2011-2384