| First Author | Kopp JL | Year | 2018 |
| Journal | Gastroenterology | Volume | 154 |
| Issue | 5 | Pages | 1509-1523.e5 |
| PubMed ID | 29273451 | Mgi Jnum | J:273682 |
| Mgi Id | MGI:6282385 | Doi | 10.1053/j.gastro.2017.12.007 |
| Citation | Kopp JL, et al. (2018) Loss of Pten and Activation of Kras Synergistically Induce Formation of Intraductal Papillary Mucinous Neoplasia From Pancreatic Ductal Cells in Mice. Gastroenterology 154(5):1509-1523.e5 |
| abstractText | 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(DeltaDuct/DeltaDuct) mice) and used Pten(DeltaDuct/+) and Pten(+/+) mice as controls. We also generated Kras(G12D);Pten(DeltaDuct/DeltaDuct) and Kras(G12D);Pten(DeltaDuct/+) 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(DeltaDuct/DeltaDuct) 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(DeltaDuct/DeltaDuct) mice developed IPMNs of several subtypes. In Pten(DeltaDuct/DeltaDuct) mice, 31.5% of IPMNs became invasive; invasion was associated with spontaneous mutations in Kras. Kras(G12D);Pten(DeltaDuct/DeltaDuct) mice all developed invasive IPMNs within 1 month. In Kras(G12D);Pten(DeltaDuct/+) 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. |
