Bardeesy Nabeel, Cheng Kuang-Hung, Berger Justin H, Chu Gerald C, Pahler Jessica, Olson Peter, Hezel Aram F, Horner James, Lauwers Gregory Y, Hanahan Douglas, DePinho Ronald A
Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Genes Dev. 2006 Nov 15;20(22):3130-46. doi: 10.1101/gad.1478706.
SMAD4 is inactivated in the majority of pancreatic ductal adenocarcinomas (PDAC) with concurrent mutational inactivation of the INK4A/ARF tumor suppressor locus and activation of the KRAS oncogene. Here, using genetically engineered mice, we determined the impact of SMAD4 deficiency on the development of the pancreas and on the initiation and/or progression of PDAC-alone or in combination with PDAC--relevant mutations. Selective SMAD4 deletion in the pancreatic epithelium had no discernable impact on pancreatic development or physiology. However, when combined with the activated KRAS(G12D) allele, SMAD4 deficiency enabled rapid progression of KRAS(G12D)-initiated neoplasms. While KRAS(G12D) alone elicited premalignant pancreatic intraepithelial neoplasia (PanIN) that progressed slowly to carcinoma, the combination of KRAS(G12D) and SMAD4 deficiency resulted in the rapid development of tumors resembling intraductal papillary mucinous neoplasia (IPMN), a precursor to PDAC in humans. SMAD4 deficiency also accelerated PDAC development of KRAS(G12D) INK4A/ARF heterozygous mice and altered the tumor phenotype; while tumors with intact SMAD4 frequently exhibited epithelial-to-mesenchymal transition (EMT), PDAC null for SMAD4 retained a differentiated histopathology with increased expression of epithelial markers. SMAD4 status in PDAC cell lines was associated with differential responses to transforming growth factor-beta (TGF-beta) in vitro with a subset of SMAD4 wild-type lines showing prominent TGF-beta-induced proliferation and migration. These results provide genetic confirmation that SMAD4 is a PDAC tumor suppressor, functioning to block the progression of KRAS(G12D)-initiated neoplasms, whereas in a subset of advanced tumors, intact SMAD4 facilitates EMT and TGF-beta-dependent growth.
在大多数胰腺导管腺癌（PDAC）中，SMAD4会发生失活，同时INK4A/ARF肿瘤抑制基因座发生突变失活，KRAS癌基因被激活。在此，我们利用基因工程小鼠，确定了SMAD4缺陷对胰腺发育以及对单独的PDAC或与PDAC相关突变联合情况下的起始和/或进展的影响。胰腺上皮中选择性缺失SMAD4对胰腺发育或生理功能没有明显影响。然而，当与激活的KRAS（G12D）等位基因结合时，SMAD4缺陷会使KRAS（G12D）引发的肿瘤迅速进展。虽然单独的KRAS（G12D）会引发癌前胰腺上皮内瘤变（PanIN），且进展缓慢至癌，但KRAS（G12D）与SMAD4缺陷的联合导致了类似导管内乳头状黏液性肿瘤（IPMN）的肿瘤快速发展，IPMN是人类PDAC的一种前体。SMAD4缺陷还加速了KRAS（G12D）INK4A/ARF杂合小鼠的PDAC发展，并改变了肿瘤表型；虽然具有完整SMAD4的肿瘤经常表现出上皮-间质转化（EMT），但SMAD4缺失的PDAC保留了分化的组织病理学特征，上皮标志物表达增加。PDAC细胞系中的SMAD4状态与体外对转化生长因子-β（TGF-β）的不同反应相关，一部分SMAD4野生型细胞系显示出显著的TGF-β诱导的增殖和迁移。这些结果提供了遗传学证据，证明SMAD4是一种PDAC肿瘤抑制因子，其功能是阻止KRAS（G12D）引发的肿瘤进展，而在一部分晚期肿瘤中，完整的SMAD4促进EMT和TGF-β依赖性生长。
