Loss of Pten and Activation of Kras Synergistically Induce Formation of Intraductal Papillary Mucinous Neoplasia From Pancreatic Ductal Cells in Mice.
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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DOI：
10.1053/j.gastro.2017.12.007
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发表时间：
2018-04
期刊：
影响因子：
29.4
通讯作者：
Sander M
中科院分区：
文献类型：
--
作者：
Kopp JL;Dubois CL;Schaeffer DF;Samani A;Taghizadeh F;Cowan RW;Rhim AD;Stiles BL;Valasek M;Sander M
导管内乳头状黏液性肿瘤（IPMN）是一种癌前囊性病变，可发展为胰腺导管腺癌（PDAC）。这些大的肉眼可见的病变在医学成像过程中经常被检测到，但尚不清楚它们如何形成或进展为PDAC。我们的目的是鉴定形成IPMN的细胞和促进IPMN发育和进展的突变。我们产生了在导管细胞中特异性破坏Pten的小鼠（Sox 9 CreERT 2;Ptenflox/flox; R26 RYFP或PtenΔDuct/ΔDuct小鼠），并使用PtenΔDuct/+和Pten+/+小鼠作为对照。我们还产生了KrasG 12 D;PtenΔDuct/ΔDuct和KrasG 12 D;PtenΔDuct/+小鼠。当小鼠为26周-14.5月龄时收集胰腺，并通过组织学、免疫组织化学和电子显微镜进行分析。我们使用多重液滴数字PCR检测PtenΔDuct/ΔDuct小鼠的自发Kras突变，并研究Ras通路激活对IPMN启动和进展的影响。我们从一位患有侵袭性胰胆IPMN的患者获得了2个胰腺切片，并通过免疫组织化学分析了有和没有侵袭性IPMN的区域（对照组织）。具有导管细胞特异性Pten破坏的小鼠而非对照小鼠出现了人IPMN的散发性、肉眼可见的导管内乳头状病变的组织学和分子特征。PtenΔDuct/ΔDuct小鼠产生了几种亚型的IPMN。在PtenΔDuct/ΔDuct小鼠中，31.5%的IPMN成为侵袭性的;侵袭与Kras的自发突变相关。KrasG 12 D;PtenΔDuct/ΔDuct小鼠均在1个月内形成侵袭性IPMN。KrasG 12 D;PtenΔDuct/+小鼠也均发生IPMN，主要为胰胆亚型，70%发生PDAC。在所有模型中，IPMN和PDAC表达导管特异性谱系追踪标记物黄色荧光蛋白。在免疫组化分析中，我们发现与健康胰腺组织相比，侵袭性人胰胆IPMN组织具有较低水平的PTEN和增加水平的磷酸化（活化）ERK。在分析小鼠导管细胞特异性破坏的Pten，有或没有激活的Kras，我们发现的证据导管细胞起源的IPMN。我们还发现，PTEN丢失和激活的Kras在促进IPMN的发展和向PDAC的进展中具有协同作用。
Intraductal papillary mucinous neoplasias (IPMN) 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. We generated mice with disruption of Pten specifically in ductal cells (Sox9CreERT2;Ptenflox/flox;R26RYFP or PtenΔDuct/ΔDuct mice) and used PtenΔDuct/+ and Pten+/+ mice as controls. We also generated KrasG12D;PtenΔDuct/ΔDuct and KrasG12D;PtenΔDuct/+ mice. Pancreata were collected when mice were 26 weeks–14.5 months old and analyzed by histology, immunohistochemistry, and electron microscopy. We performed multiplexed droplet digital PCR to detect spontaneous Kras mutations in PtenΔDuct/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. Mice with ductal cell-specific disruption of Pten but not control mice developed sporadic, macroscopic, intraductal papillary lesions histologic and molecular features of human IPMNs. PtenΔDuct/ΔDuct mice developed IPMNs several subtypes. In PtenΔDuct/ΔDuct mice, 31.5% of IPMNs became invasive; invasion was associated with spontaneous mutations in Kras. KrasG12D;PtenΔDuct/ΔDuct mice all developed invasive IPMNs within 1 month. KrasG12D;PtenΔDuct/+ mice also all developed IPMN, predominately of the pancreatobiliary subtype, and 70% 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. 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.
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