YAP and AP-1 Cooperate to Initiate Pancreatic Cancer Development from Ductal Cells in Mice

Abstract

The development of pancreatic cancer is heavily dependent upon the aberrant activation of KRAS signaling. Among the downstream targets of KRAS, the effectors of the Hippo pathway YAP and TAZ (YAP/TAZ) are crucial during cancer initiation and progression. However, little is known about the cell type-specific effects of YAP/TAZ on the development of pancreatic cancer. Here we clarify the unique consequences of YAP/TAZ activation in the ductal cell population of the pancreas by generating mice with pancreatic duct cell-specific, inducible knockouts of Lats1 and Lats2, the main kinases upstream of YAP/TAZ. Oncogenic activation of YAP by deletion of Lats1/2 in ductal cells led to the rapid transformation of the pancreas, which was accompanied by a robust increase in the expression of YAP and AP-1 target genes. Pharmacologic inhibition of AP-1 activity induced death in Lats1/2 knockout organoids and attenuated YAP-dependent transformation of the pancreas in vivo. Both YAP and AP-1 were activated during the development of KRAS-dependent cancer in mice and human patients with pancreatic ductal adenocarcinoma, suggesting that this signaling hub represents an important mediator of pancreatic cancer development and progression. Collectively, these data define a YAP-dependent mechanism of pancreatic cancer cell development and suggest that inhibition of AP-1 can suppress this development. Significance: A pancreatic ductal cell-specific knockout mouse model featuring constitutively active YAP allows for the study of YAP-dependent transformation of the pancreas and for screening pharmacologically active inhibitors.