De La O Jean-Paul, Emerson Lyska L, Goodman Jessica L, Froebe Scott C, Illum Benjamin E, Curtis Andrew B, Murtaugh L Charles
Department of Human Genetics, University of Utah, 15 North 2030 East, Room 2100, Salt Lake City, UT 84112, USA.
Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18907-12. doi: 10.1073/pnas.0810111105. Epub 2008 Nov 21.
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.
在小鼠中模拟胰腺癌的研究工作主要集中在模仿人类疾病中发现的基因变化，特别是胰腺肿瘤及其假定前体胰腺上皮内瘤变（PanIN）中出现的激活型KRAS突变。尽管激活的小鼠Kras突变会诱导出与人类相似的PanIN病变，但只有一小部分表达突变Kras的细胞会继续形成PanIN。这种选择性反应的基础尚不清楚，同样不清楚成熟胰腺中的哪些细胞类型实际上对PanIN的形成有贡献。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，PanIN表现出活跃的Notch信号。我们假设，在胚胎胰腺中抑制分化的Notch，通过废除肿瘤起始细胞的正常分化程序，促进了PanIN的形成。通过在小鼠胰腺中的条件性表达，我们发现在诱导PanIN形成方面，激活的Notch和Kras之间存在显著的协同作用。此外，我们发现成熟腺泡细胞中的Kras激活会诱导出与普遍Kras激活时所见相同的PanIN病变，并且Notch促进了这些腺泡来源的PanIN的起始和发育异常进展，尽管尚未发展为浸润性腺癌。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，这就解释了一种典型的导管肿瘤如何从非导管腺泡细胞中产生。
