A novel pancreatic cancer model originated from transformation of acinar cells in adult tree shrew, a primate-like animal.

Pancreatic cancer is one of the most lethal common cancer. The cell-of-origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial and recent progress suggested acinar cells as a most probable candidate. However, the genetic alterations driving the transformation of pancreatic acinar cells in fully mature animals remain to be deciphered. In this study, lentivirus was used as a tool to introduce genetic engineering in tree shrew pancreatic acinar cells to explore the driver mutation essential for malignant transformation and to establish a novel tree shrew PDAC model, because we found that lentivirus could selectively infect acinar cells in tree shrew pancreas. Combination of oncogenic KRAS G12D expression and inactivation of tumor suppressor genes Tp53 , Cdkn2a and Cdkn2b could induce pancreatic cancer with full penetrance. Silencing of Cdkn2b is indispensable for Rb1 phosphorylation and tumor induction. The tree shrew PDAC possess main histological and molecular features of human PDAC. Gene expression profile of tree shrew PDAC was more similar to human disease than a mouse model. In conclusion, we established a novel pancreatic cancer model in tree shrew and identified driver mutations indispensable for PDAC induction from acinar cells in mature adults, and also demonstrated the essential roles of Cdkn2b in the induction of PDAC originating from adult acinar cell. It may provide a better choice for PDAC model derived from acinar cells in fully mature animals.