Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma.

摘要: Pancreatic ductal adenocarcinoma ranks among the most lethal of human malignancies. Here, we assess cooperative interactions two signature mutations in mice engineered to sustain pancreas-specific Cre-mediated activation a mutant Kras allele (KrasG12D) and deletion conditional Ink4a/Arf tumor suppressor allele. The phenotypic impact KrasG12D alone was limited primarily development focal premalignant lesions, termed pancreatic intraepithelial neoplasias (PanINs), whereas sole inactivation failed produce any neoplastic lesions pancreas. In combination, expression deficiency resulted an earlier appearance PanIN these neoplasms progressed rapidly highly invasive metastatic cancers, resulting death all cases by 11 weeks. evolution tumors bears striking resemblance disease, possessing proliferative stromal component with propensity advance poorly differentiated state. These findings mouse provide experimental support for widely accepted model which activated KRAS serves initiate INK4A/ARF suppressors function constrain malignant conversion into adenocarcinoma. This faithful may permit systematic analysis genetic implicated disease serve as platform identification early markers efficient testing novel therapies.