Objective Pancreatic 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 Kras G12D mutation with an additional gene mutation known to occur in human IPMN can induce IPMN from pancreatic duct cells. Design We 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. Results Activating Kras G12D 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. Conclusion Our work demonstrates that IPMN can result from synergy between Kras G12D 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.

中文翻译：

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Kras 和 Lkb1 突变协同诱导源自胰管细胞的导管内乳头状粘液性肿瘤

目的 胰腺癌可由称为导管内乳头状黏液性肿瘤 (IPMN) 的前体病变引起，其特征是含有乳头和粘液产生细胞的囊肿。IPMN 中 KRAS 突变的高频率和组织学分析表明致癌 KRAS 驱动了胰管细胞的 IPMN 发展。然而，导管细胞中 Kras 突变的诱导不足以产生 IPMN，并且仍然缺少 IPMN 导管起源的正式证据。在这里，我们探讨了将致癌 Kras G12D 突变与已知发生在人类 IPMN 中的额外基因突变相结合是否可以从胰管细胞诱导 IPMN。设计 我们创建并表型分析了小鼠模型，其中使用 Cre 介导的基因重组在胰管中有条件地诱导 Kras 和肿瘤抑制基因肝激酶 B1 (Lkb1/Stk11) 中的突变。我们还测试了 β-连环蛋白抑制在病变形成过程中的作用。结果 激活 Kras G12D 突变和 Lkb1 失活协同诱导 IPMN，主要是胃型并具有恶性潜能。小鼠病变与人类 IPMN 共享几个特征。时间进程分析表明 IPMN 由导管内乳头和腺体肿瘤发展而来，这两种肿瘤都源自大胰管内衬的上皮。β-连环蛋白是 IPMN 中腺体肿瘤的发展和随后粘液细胞的发展所必需的。反而，β-连环蛋白的缺乏不会阻碍 IPMN 中导管内乳头的形成及其向乳头状病变的进展。结论 我们的工作表明 IPMN 可以由 Kras G12D 突变和抑癌基因失活之间的协同作用产生。导管上皮可引起腺体肿瘤和乳头状病变，这两者都可能导致 IPMN 的形成。