Pancreatic HIF2α Stabilization Leads to Chronic Pancreatitis and Predisposes to Mucinous Cystic Neoplasm

Abstract

Background & AimsTissue 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 HIF2α. Previous studies of HIF action in the pancreas have relied on loss-of-function mouse models, and the effects of HIF2α expression in the pancreas have remained undefined.MethodsWe developed several transgenic mouse models based on the expression of an oxygen-stable form of HIF2α, 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 KrasG12D in the pancreas.ResultsWe show that HIF2α 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 HIF2α in mouse pancreata led to the development of chronic pancreatitis. Importantly, pancreatic HIF1α stabilization did not disrupt the pancreatic parenchyma, indicating that the chronic pancreatitis phenotype is specific to HIF2α. In the presence of oncogenic Kras, HIF2α 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.ConclusionsWe show that pancreatic HIF2α 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.

Fibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and Therapeutic Targets

“…Fibroblasts accumulate in the pancreas during acute and chronic pancreatitis 18 , as well as in early pre-invasive lesions such as pancreatic intraepithelial neoplasms (PanIN), mucinous cystic neoplasms (MCN) and intraductal papillary mucinous neoplasms (IPMN) [19][20][21][22][23][24][25] , but increased numbers are seen in PDA. The fibrotic responses likely originate from the activation and subsequent expansion of local, so-called quiescent pancreatic stellate cells (PSC), but infiltration of fibroblasts derived from mesenchymal precursors in the circulation may also occur 26 .…”

Hif1α Deletion Limits Tissue Regeneration via Aberrant B Cell Accumulation in Experimental Pancreatitis

“…Our observations support the notion that HIF1α, a key regulator of hypoxic adaptations, promotes the regenerative processes of damaged, inflamed, and hypoxic pancreata to regain tissue integrity and homeostasis. Of note, two recent studies have reported contribution of HIF1α to intrapancreatic coagulation and injury response during experimental acute pancreatitis (Park et al, 2018), and onset of chronic pancreatitis by HIF2α overexpression in mice (Schofield et al, 2018). These results, along with our findings suggest that hypoxia affects multiple biological aspects of pancreatitis, and the two HIFα isoforms play distinct roles in this disease.…”

GEMMs Are a Gem When it Comes to Defining the Role of HIF2α in Mucinous Cystic Neoplasms

“…In this issue of Cellular and Molecular Gastroenterology and Hepatology , Schofield et al 5 implemented a complementary, 2-prong approach to reveal that homeostasis within the pancreas may depend on hypoxic signaling pathways. Generation and characterization of several novel murine strains that coupled expression of oncogenic KRAS with the constitutive expression or repression of HIF2α demonstrated a clear impact of the hypoxia signaling pathway in precursor chronic pancreatitis and MCN development.…”

“…To address this key gap, Schofield et al 5 revealed that mice generated with the pancreas-lineage-specific expression of the oxygen-stable form of HIF2α are born with histologically normal pancreata. However, by as early as 2 weeks of age, there is an increase in proliferative cells, onset of fibrosis, abundant immune cell infiltration, and a shift in the cytokine profile, all phenotypic hallmarks consistent with chronic pancreatitis.…”

“…Additionally, GEMMs facilitate the understanding of the drivers of disease inception to the mechanisms behind disease progression and metastasis. Together, the GEMMs generated and characterized by Schofield et al 5 have used new state-of-the art model systems to characterize novel molecular insights into the progression of pancreatic cancer.…”