Loss of pten and activation of kras synergistically induce formation of intraductal papillary mucinous neoplasia from pancreatic ductal cells in mice

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Item Type:	Article
Title:	Loss of pten and activation of kras synergistically induce formation of intraductal papillary mucinous neoplasia from pancreatic ductal cells in mice
Creators Name:	Kopp, J.L., Dubois, C.L., Schaeffer, D.F., Samani, A., Taghizadeh, F., Cowan, R.W., Rhim, A.D., Stiles, B.L., Valasek, M. and Sander, M.
Abstract:	BACKGROUND & AIMS: Intraductal papillary mucinous neoplasias (IPMNs) are precancerous cystic lesions that can develop into pancreatic ductal adenocarcinomas (PDACs). These large macroscopic lesions are frequently detected during medical imaging, but it is unclear how they form or progress to PDAC. We aimed to identify cells that form IPMNs and mutations that promote IPMN development and progression. METHODS: We generated mice with disruption of Pten specifically in ductal cells (Sox9CreER(T2);Pten(flox/flox);R26R(YFP) or Pten(ΔDuct/ΔDuct) mice) and used Pten(ΔDuct/+) and Pten(+/+) mice as controls. We also generated Kras(G12D);Pten(ΔDuct/ΔDuct) and Kras(G12D);Pten(ΔDuct/+) mice. Pancreata were collected when mice were 28 weeks to 14.5 months old and analyzed by histology, immunohistochemistry, and electron microscopy. We performed multiplexed droplet digital polymerase chain reaction to detect spontaneous Kras mutations in Pten(ΔDuct/ΔDuct) mice and study the effects of Ras pathway activation on initiation and progression of IPMNs. We obtained 2 pancreatic sections from a patient with an invasive pancreatobiliary IPMN and analyzed the regions with and without the invasive IPMN (control tissue) by immunohistochemistry. RESULTS: Mice with ductal cell-specific disruption of Pten but not control mice developed sporadic, macroscopic, intraductal papillary lesions with histologic and molecular features of human IPMNs. Pten(ΔDuct/ΔDuct) mice developed IPMNs of several subtypes. In Pten(ΔDuct/ΔDuct) mice, 31.5% of IPMNs became invasive; invasion was associated with spontaneous mutations in Kras. Kras(G12D);Pten(ΔDuct/ΔDuct) mice all developed invasive IPMNs within 1 month. In Kras(G12D);Pten(ΔDuct/+) mice, 70% developed IPMN, predominately of the pancreatobiliary subtype, and 63.3% developed PDAC. In all models, IPMNs and PDAC expressed the duct-specific lineage tracing marker yellow fluorescent protein. In immunohistochemical analyses, we found that the invasive human pancreatobiliary IPMN tissue had lower levels of PTEN and increased levels of phosphorylated (activated) ERK compared with healthy pancreatic tissue. CONCLUSIONS: In analyses of mice with ductal cell-specific disruption of Pten, with or without activated Kras, we found evidence for a ductal cell origin of IPMNs. We also showed that PTEN loss and activated Kras have synergistic effects in promoting development of IPMN and progression to PDAC.
Keywords:	Pancreatic Ductal Carcinoma, Cell Lineage, Cell Movement, Cell Proliferation, Neoplastic Cell Transformation, Disease Progression, Enzymologic Gene Expression Regulation, Neoplastic Gene Expression Regulation, Genetic Predisposition to Disease, Inbred C57BL Mice, Knockout Mice, Mutation, Neoplasm Invasiveness, Cystic, Mucinous and Serous Neoplasms, PTEN Phosphohydrolase, Pancreatic Ducts, Pancreatic Neoplasms, Phenotype, Proto-Oncogene Proteins p21(ras), Signal Transduction, Time Factors, Animals, Mice
Source:	Gastroenterology
ISSN:	0016-5085
Publisher:	Elsevier
Volume:	154
Number:	5
Page Range:	1509-1523.e5
Date:	April 2018
Additional Information:	Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
Official Publication:	https://doi.org/10.1053/j.gastro.2017.12.007
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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