Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia
Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia
复制标题
DOI：
10.1073/pnas.0810111105
复制
发表时间：
2008-12-02
影响因子：
11.1
通讯作者：
Murtaugh, L. Charles
中科院分区：
文献类型：
--
作者：
Jean-Paul, De La O.;Emerson, Lyska L.;Murtaugh, L. Charles
在小鼠中建立胰腺癌模型的努力主要集中在模拟人类疾病中发现的基因变化，特别是在胰腺肿瘤及其可能的前体-胰腺上皮内瘤变(Panin)中发生的激活KRAS突变。尽管激活的小鼠Kras突变会引起与人类相似的Panin损伤，但只有少数表达突变Kras的细胞会继续形成Panins。这种选择性反应的基础尚不清楚，同样也不清楚成熟胰腺中的哪些细胞类型实际上对Panins有贡献。一条线索来自于这样一个事实，即与成年胰腺中的大多数细胞不同，Panins显示出活跃的Notch信号。我们假设，抑制胚胎胰腺分化的Notch通过取消启动肿瘤细胞的正常分化程序而促进Panin的形成。通过在小鼠胰腺中的条件表达，我们发现激活的Notch和Kras在诱导Panin形成方面具有戏剧性的协同作用。此外，我们发现成熟的腺泡细胞中Kras的激活诱导了与普遍存在的Kras激活相同的Panin病变，并且Notch促进了这些腺泡来源的Panin的启动和发育异常进展，尽管没有侵袭性腺癌。在细胞水平上，Notch/Kras共激活促进腺泡细胞快速重编程为导管样表型，为特征性导管肿瘤如何起源于非导管腺泡细胞提供了解释。
Efforts to model pancreatic cancer in mice have focused on mimicking genetic changes found in the human disease, particularly the activating KRAS mutations that occur in pancreatic tumors and their putative precursors, pancreatic intraepithelial neoplasia (PanIN). Although activated mouse Kras mutations induce PanIN lesions similar to those of human, only a small minority of cells that express mutant Kras go on to form PanINs. The basis for this selective response is unknown, and it is similarly unknown what cell types in the mature pancreas actually contribute to PanINs. One clue comes from the fact that PanINs, unlike most cells in the adult pancreas, exhibit active Notch signaling. We hypothesize that Notch, which inhibits differentiation in the embryonic pancreas, contributes to PanIN formation by abrogating the normal differentiation program of tumor-initiating cells. Through conditional expression in the mouse pancreas, we find dramatic synergy between activated Notch and Kras in inducing PanIN formation. Furthermore, we find that Kras activation in mature acinar cells induces PanIN lesions identical to those seen upon ubiquitous Kras activation, and that Notch promotes both initiation and dysplastic progression of these acinar-derived PanINs, albeit short of invasive adenocarcinoma. At the cellular level, Notch/Kras coactivation promotes rapid reprogramming of acinar cells to a duct-like phenotype, providing an explanation for how a characteristically ductal tumor can arise from nonductal acinar cells.