Our pancreas has two main functions, endocrine control of blood sugar and exocrine production of the enzymes that digest our food. These enzymes are synthesized by pancreatic acinar cells and transported to the intestine through a network of pancreatic duct cells. Pancreatic cancer, the third deadliest cancer in the U.S., was previously assumed, based on histology and gene expression, to arise from duct cells.
However, research in the Murtaugh lab demonstrated that this cancer instead arises from fully differentiated acinar cells. This process requires a dramatic reprogramming of cellular function, resulting from the downregulation of the transcription factor Ptf1a, which is a rate-limiting step in pancreatic cancer development. The Murtaugh lab has found that reactivating Ptf1a in mouse and human pancreatic cancer induces re-differentiation and inhibits growth, and is pursuing this as a novel therapeutic approach.
The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. Krah NM, De La O JP, Swift GH, Hoang CQ, Willet SG, Chen Pan F, Cash GM, Bronner MP, Wright CV, MacDonald RJ, Murtaugh LC. Elife. 2015 Jul;4. pii 07125.
Prevention and reversion of pancreatic tumorigenesis through a differentiation-based mechanism. Krah NM, Narayanan SM, Yugawa DE, Straley JA, Wright CVE, MacDonald RJ, Murtaugh LC. Dev Cell. 2019 Sep;50(6):744.