The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma

Pancreatic cancer is one of the most lethal forms of cancer, with fewer than 20% of people surviving for longer than twelve months after diagnosis. Two types of genetic mutation play important roles in pancreatic cancer. First, genes called oncogenes can be activated by mutations to drive unscheduled cell division. Second, the genes for tumor suppressors—proteins that prevent cells from dividing when they should not—can be switched off due to other mutations. Together, these mutations cause cells to over-proliferate and disrupt the structure of the pancreas. In a healthy pancreas, several different cell types perform various roles: acinar cells produce proteins that digest food, ductal cells carry these proteins to the intestine, and β cells produce insulin. Certain proteins are responsible for telling each of these cells what tasks to perform, which defines their so-called differentiation state. The protein PTF1A is crucial for establishing the differentiation state of acinar cells. In the most common form of pancreatic cancer, acinar cells are reprogrammed to become ductal cells. Moreover, pancreatic cancer cells contain much lower levels of PTF1A than normal pancreatic cells. To explore the connection between PTF1A and pancreatic cancer, Krah et al. deleted the gene for PTF1A in mice. This led to acinar cells being reprogrammed to become ductal cells. Additionally, when an oncogene mutation was activated at the same time as the gene for PTF1A was deleted, Krah et al. observed the rapid formation of large numbers of malignant pancreatic tumors in the mice. PTF1A therefore protects against pancreatic cancer by acting as a tumor suppressor and keeping acinar cells in their healthy, differentiated state. Unlike other tumor suppressors, however, PTF1A levels are reduced in cancer cells by a mechanism that does not involve a genetic mutation. Therefore, a future challenge is to determine how the amount of PTF1A protein is reduced, and in the longer term, to explore if it is possible to reverse cancer progression by forcing cancer cells back into their original differentiation state.