Pancreatic cancer is one of the most lethal common cancers. The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial, and recent evidence suggested acinar cells as the most probable candidate. However, the genetic alterations driving the transformation of pancreatic acinar cells in fully mature animals remain to be deciphered. In this study, lentivirus was used as a tool to introduce genetic engineering in tree shrew pancreatic acinar cells to explore the driver mutation essential for malignant transformation, establishing a novel tree shrew PDAC model, because we found that lentivirus could selectively infect acinar cells in tree shrew pancreas. Combination of oncogenic KRAS^G12D expression and inactivation of tumor suppressor genes Tp53, Cdkn2a and Cdkn2b could induce pancreatic cancer with full penetrance. Silencing of Cdkn2b is indispensable for Rb1 phosphorylation and tumor induction. Tree shrew PDAC possesses the main histological and molecular features of human PDAC. The gene expression profile of tree shrew PDAC was more similar to human disease than a mouse model. In conclusion, we established a novel pancreatic cancer model in tree shrew and identified driver mutations indispensable for PDAC induction from acinar cells in mature adults, demonstrating the essential roles of Cdkn2b in the induction of PDAC originating from adult acinar cells. Tree shrew could thus provide a better choice than mouse for a PDAC model derived from acinar cells in fully mature animals.

中文翻译：

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一种新颖的胰腺癌模型起源于成年树sh（一种灵长类动物）中腺泡细胞的转化。

胰腺癌是最致命的常见癌症之一。胰腺导管腺癌（PDAC）的起源细胞一直存在争议，最近的证据表明腺泡细胞是最可能的候选细胞。然而，在完全成熟的动物中驱动胰腺腺泡细胞转化的遗传改变仍有待研究。在这项研究中，慢病毒被用作在树sh胰腺腺泡细胞中引入基因工程以探索恶性转化所必需的驱动程序突变的工具，从而建立了新的树sh PDAC模型，因为我们发现慢病毒可以选择性感染树中的腺泡细胞。 rew胰腺。致癌性KRAS ^G12D表达与抑癌基因Tp53失活的结合，Cdkn2a和Cdkn2b可以诱导胰腺癌的完全外显。Cdkn2b沉默对于Rb1磷酸化和肿瘤诱导必不可少。树木sh PDAC具有人类PDAC的主要组织学和分子特征。树sh PDAC的基因表达谱比小鼠模型更类似于人类疾病。总之，我们在树sh中建立了一种新型的胰腺癌模型，并确定了成年成年腺泡细胞诱导PDAC不可缺少的驱动程序突变，证明了Cdkn2b在成年成腺泡细胞诱导PDAC中的重要作用。因此，对于完全成熟的动物中来自腺泡细胞的PDAC模型，树sh可能比小鼠提供更好的选择。