Pancreatic HIF2 alpha Stabilization Leads to Chronic Pancreatitis and Predisposes to Mucinous Cystic Neoplasm

BACKGROUND & AIMS: Tissue hypoxia controls cell differentiation in the embryonic pancreas, and promotes tumor growth in pancreatic cancer. The cellular response to hypoxia is controlled by the hypoxia-inducible factor (HIF) proteins, including HIF2 alpha. Previous studies of HIF action in the pancreas have relied on loss-of-function mouse models, and the effects of HIF2 alpha expression in the pancreas have remained undefined. METHODS: We developed several transgenic mouse models based on the expression of an oxygen-stable form of HIF2 alpha, or indirect stabilization of HIF proteins though deletion of von Hippel-Lindau, thus preventing HIF degradation. Furthermore, we crossed both sets of animals into mice expressing oncogenic Kras(G12D) in the pancreas. RESULTS: We show that HIF2 alpha is not expressed in the normal human pancreas, however, it is up-regulated in human chronic pancreatitis. Deletion of von Hippel-Lindau or stabilization of HIF2 alpha in mouse pancreata led to the development of chronic pancreatitis. Importantly, pancreatic HIF1 alpha stabilization did not disrupt the pancreatic parenchyma, indicating that the chronic pancreatitis phenotype is specific to HIF2 alpha. In the presence of oncogenic Kras, HIF2 alpha stabilization drove the formation of cysts resembling mucinous cystic neoplasm (MCN) in humans. Mechanistically, we show that the pancreatitis phenotype is linked to expression of multiple inflammatory cytokines and activation of the unfolded protein response. Conversely, MCN formation is linked to activation of Wnt signaling, a feature of human MCN. CONCLUSIONS: We show that pancreatic HIF2 alpha stabilization disrupts pancreatic homeostasis, leading to chronic pancreatitis, and, in the context of oncogenic Kras, MCN formation. These findings provide new mouse models of both chronic pancreatitis and MCN, as well as illustrate the importance of hypoxia signaling in the pancreas.