KrasandLkb1mutations synergistically induce intraductal papillary mucinous neoplasm derived from pancreatic duct cells

Abstract

ObjectivePancreatic cancer can arise from precursor lesions called intraductal papillary mucinous neoplasms (IPMN), which are characterised by cysts containing papillae and mucus-producing cells. The high frequency of KRAS mutations in IPMN and histological analyses suggest that oncogenic KRAS drives IPMN development from pancreatic duct cells. However, induction of Kras mutation in ductal cells is not sufficient to generate IPMN, and formal proof of a ductal origin of IPMN is still missing. Here we explore whether combining oncogenic KrasG12D mutation with an additional gene mutation known to occur in human IPMN can induce IPMN from pancreatic duct cells.DesignWe created and phenotyped mouse models in which mutations in Kras and in the tumour suppressor gene liver kinase B1 (Lkb1/Stk11) are conditionally induced in pancreatic ducts using Cre-mediated gene recombination. We also tested the effect of β-catenin inhibition during formation of the lesions.ResultsActivating KrasG12D mutation and Lkb1 inactivation synergised to induce IPMN, mainly of gastric type and with malignant potential. The mouse lesions shared several features with human IPMN. Time course analysis suggested that IPMN developed from intraductal papillae and glandular neoplasms, which both derived from the epithelium lining large pancreatic ducts. β-catenin was required for the development of glandular neoplasms and subsequent development of the mucinous cells in IPMN. Instead, the lack of β-catenin did not impede formation of intraductal papillae and their progression to papillary lesions in IPMN.ConclusionOur work demonstrates that IPMN can result from synergy between KrasG12D mutation and inactivation of a tumour suppressor gene. The ductal epithelium can give rise to glandular neoplasms and papillary lesions, which probably both contribute to IPMN formation.

Carcinogenesis of Pancreatic Ductal Adenocarcinoma

“…Interestingly, in most models with duct cell-specific expression of oncogenic Kras, the resulting neoplasia either resembled IPMNs or otherwise bypassed low-grade PanINs. [31][32][33]36 This suggests that in some genetic contexts, the pattern of neoplastic progression differs, based on the cell type in which oncogenic Kras is expressed.…”

Epithelial Nr5a2 heterozygosity cooperates with mutant Kras in the development of pancreatic cystic lesions

“…The massive replacement of the pancreas by cysts in KPN +/− mice is of relevance given the increasing diagnosis of pancreatic cysts, providing a new mouse model for these lesions. Other GEMMs recently used to study pancreatic cysts/IPMNs are based on the activation of mutant GNAS and KRAS in pancreatic progenitors, leading to IPMN and PDAC [5] or the deletion of LKB1 [57,58], PTEN (with or without mutant KRAS ) [59], BRG1 [55], or FBW7 [15] in ductal cells. Whether cystic lesions from KPN +/− mice show deregulated PTEN, LKB1 or BRG1 expression, or acquire GNAS mutations, remains to be elucidated.…”

“…I Cobo et al leading to IPMN and PDAC [5] or the deletion of LKB1 [57,58], PTEN (with or without mutant KRAS) [59], BRG1 [55], or FBW7 [15] in ductal cells. Whether cystic lesions from KPN +/− mice show deregulated PTEN, LKB1 or BRG1 expression, or acquire GNAS mutations, remains to be elucidated.…”

Intraductal Pancreatic Mucinous Neoplasms: A Tumor-Biology Based Approach for Risk Stratification

“…The role of KRAS in PDAC and other human cancers is well established [69]; mutations in this gene are an early event during IPMN development and are present in up to 80% of the cases [5,[70][71][72]. A recent study confirmed the synergistic action of KRAS and tumor suppressor gene mutations for development of IPMN in animal model and highlighted the role of Wnt/β-catenin pathway in KRAS-associated lesions [73].…”