Liu Xin, Pitarresi Jason R, Cuitiño Maria C, Kladney Raleigh D, Woelke Sarah A, Sizemore Gina M, Nayak Sunayana G, Egriboz Onur, Schweickert Patrick G, Yu Lianbo, Trela Stefan, Schilling Daniel J, Halloran Shannon K, Li Maokun, Dutta Shourik, Fernandez Soledad A, Rosol Thomas J, Lesinski Gregory B, Shakya Reena, Ludwig Thomas, Konieczny Stephen F, Leone Gustavo, Wu Jinghai, Ostrowski Michael C
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio 43210, USA;
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA;
Genes Dev. 2016 Sep 1;30(17):1943-55. doi: 10.1101/gad.283499.116. Epub 2016 Sep 15.
The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model increased ADM. Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfa) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM. The mechanism involved activation of AKT and noncanonical activation of the GLI family transcription factor GLI2. GLI2 was phosphorylated at Ser230 in an AKT-dependent fashion and directly regulated Tgfa expression in fibroblasts lacking Smo Additionally, Smo-deleted fibroblasts stimulated the growth of Kras(G12D)/Tp53(R172H) pancreatic tumor cells in vivo and in vitro. These results define a non-cell-autonomous mechanism modulating Kras(G12D)-driven ADM that is balanced by cross-talk between Hedgehog/SMO and AKT/GLI2 pathways in stromal fibroblasts.
微环境对胰腺腺泡-导管化生（ADM）的影响目前尚不清楚，ADM是致癌性Kras驱动的胰腺癌进展过程中的一种癌前转变。在此，我们发现在Kras（G12D）小鼠模型中，通过基因敲除基质成纤维细胞中的平滑肌瘤（Smo）来破坏旁分泌Hedgehog信号通路会增加ADM。缺失Smo的成纤维细胞中转化生长因子-α（Tgfa）mRNA表达较高，分泌的TGFα水平也较高，从而导致腺泡细胞中EGFR信号通路激活并增加ADM。其机制涉及AKT的激活和GLI家族转录因子GLI2的非经典激活。GLI2以AKT依赖的方式在Ser230位点磷酸化，并直接调节缺乏Smo的成纤维细胞中Tgfa的表达。此外，缺失Smo的成纤维细胞在体内和体外均可刺激Kras（G12D）/Tp53（R172H）胰腺肿瘤细胞的生长。这些结果定义了一种非细胞自主机制，该机制通过基质成纤维细胞中Hedgehog/SMO和AKT/GLI2通路之间的相互作用来调节Kras（G12D）驱动的ADM。
