| Pancreatic cancer is one of the most lethal human malignancies with an annual incidence rate of approximately 44,000 cases. The initiation and progression of pancreatic cancer is a multi-step process involving genetic changes in critical tumor susceptibility loci. Amplification of the c-Myc gene has been reported in a significant subset of primary PDACs and in more than half of pancreatic cancer cell lines. In line with these published reports, we show that the c-Myc protein is upregulated in the early pancreatic precursor lesions as well as primary and metastatic PDACs. To assess the role of c-Myc during pancreatic tumor initiation and progression, we developed a novel mouse model that allows a strong, ligand-controlled expression of any given gene of interest in a temporally controlled manner in the pancreas. Using this unique mouse model, we demonstrated that the upregulation of c-Myc was sufficient to cause rapid transformation and the appearance of ductal neoplasia after a short latency period. These neoplastic lesions progressed into primary PDACs with sporadic metastases to the liver. The treatment of tumor-bearing mice with a ligand (doxycycline) resulted in the suppression of c-Myc expression, which subsequently led to apoptosis of neoplastic cells within PanIN lesions and primary tumors. Heterozygous deletion of Cdkn2a (Ink4a/Arf) promoted the progression of c-Myc-induced neoplasms, resulting in a higher incidence of PDACs and greater propensity for distant metastases. The subsequent suppression of c-Myc expression caused rapid regression of primary PDACs and liver metastases in wildtype or a heterozygous Cdkn2a knockout background. These results indicate that c-Myc is required for the growth and survival of neoplastic cells both in the absence and presence of tumor suppressor genes. Furthermore, we identified a subset of cancer cells within primary tumors that remained dormant following tumor regression. These cells display cell surface markers that have been associated with stem cells, and might serve as cancer-initiating cells that are responsible for disease recurrence. |
