The role of yes-associated protein (YAP) in duct cell-derived cancer in the pancreas and liver

Abstract

The Hippo pathway is crucial during development and in maintaining homeostasis in various organs. YAP/TAZ, the effectors of the Hippo pathway, are known to play important roles not only in regulating homeostasis, but also in cancer development. Pancreatic cancer is one of the most lethal cancers in which the targeted therapy remains challenging. The origin-of-cell of pancreatic cancer have been believed to be acinar cells retaining Kras mutation, however, several studies have successfully proven that Kras can drive pancreatic cancer development from duct cells. Although YAP is proven to be a critical mediator in the downstream of aberrant Kras signaling in pancreatic cancer development, the role of YAP and direct consequence of YAP activation in ductal cell population has not yet been underscored. Here, I focused on duct cells as the origin of pancreatic cancer, demonstrating that YAP drives pancreatic cancer from the ductal cell population utilizing ductal cell specific Lats1/2 mutant mouse model via crossing Sox9-Cre/ERT2 mouse with Lats1 and Lats2 conditional knockout mouse model. Mechanistically, ductal cell derived pancreatic cancer driven by YAP cooperates with AP-1. Additionally, I found ductal cell specific activation of YAP induced cholangiocarcinoma from bile ducts in the liver, which share the developmental origin with pancreatic ducts.