Departments of Pediatrics and Cellular and Molecular Medicine, University of California-San Diego, La Jolla, CA 92093-0695, USA.
Cancer Cell. 2012 Dec 11;22(6):737-50. doi: 10.1016/j.ccr.2012.10.025. Epub 2012 Nov 29.
Tumors are largely classified by histologic appearance, yet morphologic features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.
肿瘤主要通过组织学外观进行分类，但形态特征不一定能预测细胞起源。为了确定胰腺导管腺癌（PDA）的起源，我们在诱导 PDA 起始性 Kras 突变后标记和追踪胰腺细胞群体。我们的研究表明，导管和干细胞样中央腺泡细胞出人意料地对致癌转化具有抗性，而腺泡细胞很容易形成具有导管特征的 PDA 前体病变。我们表明，腺泡衍生的癌前病变的形成取决于导管基因 Sox9 的异位诱导。此外，当与致癌性 Kras 同时表达时，Sox9 加速了癌前病变的形成。这些结果提供了对 PDA 细胞起源的深入了解，并表明其前体是通过在腺泡细胞中诱导类似导管的状态而产生的。
