Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar-ductal metaplasia.
Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar-ductal metaplasia.
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DOI：
10.1101/gad.283499.116
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发表时间：
2016-09-01
影响因子：
10.5
通讯作者：
Ostrowski MC
中科院分区：
文献类型：
--
作者：
Liu X;Pitarresi JR;Cuitiño MC;Kladney RD;Woelke SA;Sizemore GM;Nayak SG;Egriboz O;Schweickert PG;Yu L;Trela S;Schilling DJ;Halloran SK;Li M;Dutta S;Fernandez SA;Rosol TJ;Lesinski GB;Shakya R;Ludwig T;Konieczny SF;Leone G;Wu J;Ostrowski MC
Liu等人的研究表明，KrasG12D小鼠模型中，通过基因消融间质成纤维细胞Smoothened （Smo）来破坏旁分泌Hedgehog信号会增加腺泡到导管化生（ADM）。smo缺失的成纤维细胞表达更高的转化生长因子-α (Tgfα) mRNA，分泌更高水平的Tgfα，导致腺泡细胞中EGFR信号的激活和ADM的增加。微环境对胰腺腺泡到导管化生（ADM）的贡献目前尚不清楚，这是kras驱动的胰腺癌进展中的癌前转变。在KrasG12D小鼠模型中，我们发现通过基因消融Smoothened （Smo）破坏间质成纤维细胞旁分泌的Hedgehog信号会增加adm， Smo缺失的成纤维细胞表达更高的转化生长因子-α (Tgfa) mRNA并分泌更高水平的TGFα，导致腺泡细胞中EGFR信号的激活和adm的增加，其机制涉及AKT的激活和GLI家族转录因子GLI2的非典型激活。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，smo缺失的成纤维细胞在体内和体外刺激KrasG12D/Tp53R172H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，调节krasg12d驱动的ADM，该机制通过间质成纤维细胞中Hedgehog/SMO和AKT/GLI2通路之间的串扰来平衡。
Liu et al. show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a KrasG12D mouse model increased acinar-to-ductal metaplasia (ADM). Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfα) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM. 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 KrasG12D 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 KrasG12D/Tp53R172H pancreatic tumor cells in vivo and in vitro. These results define a non-cell-autonomous mechanism modulating KrasG12D-driven ADM that is balanced by cross-talk between Hedgehog/SMO and AKT/GLI2 pathways in stromal fibroblasts.
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