Wu Jinghai, Liu Xin, Nayak Sunayana G, Pitarresi Jason R, Cuitiño Maria C, Yu Lianbo, Hildreth Blake E, Thies Katie A, Schilling Daniel J, Fernandez Soledad A, Leone Gustavo, Ostrowski Michael C
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio, United States of America.
PLoS One. 2017 Sep 21;12(9):e0184984. doi: 10.1371/journal.pone.0184984. eCollection 2017.
The contribution of the tumor microenvironment to the development of pancreatic adenocarcinoma (PDAC) is unclear. The LSL-KrasG12D/+;LSL-p53R172H/+;Pdx-1-Cre (KPC) tumor model, which is widely utilized to faithfully recapitulate human pancreatic cancer, depends on Cre-mediated recombination in the epithelial lineage to drive tumorigenesis. Therefore, specific Cre-loxP recombination in stromal cells cannot be applied in this model, limiting the in vivo investigation of stromal genetics in tumor initiation and progression. To address this issue, we generated a new Pdx1FlpO knock-in mouse line, which represents the first mouse model to physiologically express FlpO recombinase in pancreatic epithelial cells. This mouse specifically recombines Frt loci in pancreatic epithelial cells, including acinar, ductal, and islet cells. When combined with the Frt-STOP-Frt KrasG12D and p53Frt mouse lines, simultaneous Pdx1FlpO activation of mutant Kras and deletion of p53 results in the spectrum of pathologic changes seen in PDAC, including PanIN lesions and ductal carcinoma. Combination of this KPF mouse model with any stroma-specific Cre can be used to conditionally modify target genes of interest. This will provide an excellent in vivo tool to study the roles of genes in different cell types and multiple cell compartments within the pancreatic tumor microenvironment.
肿瘤微环境对胰腺腺癌（PDAC）发展的贡献尚不清楚。LSL-KrasG12D/+;LSL-p53R172H/+;Pdx-1-Cre（KPC）肿瘤模型被广泛用于忠实地重现人类胰腺癌，它依赖上皮谱系中的Cre介导重组来驱动肿瘤发生。因此，无法在该模型中应用基质细胞中的特异性Cre-loxP重组，这限制了对肿瘤起始和进展过程中基质遗传学的体内研究。为了解决这个问题，我们构建了一种新的Pdx1FlpO基因敲入小鼠品系，这是首个在胰腺上皮细胞中生理性表达FlpO重组酶的小鼠模型。该小鼠在胰腺上皮细胞（包括腺泡细胞、导管细胞和胰岛细胞）中特异性重组Frt位点。当与Frt-STOP-Frt KrasG12D和p53Frt小鼠品系结合时，Pdx1FlpO同时激活突变型Kras和缺失p53会导致PDAC中出现一系列病理变化，包括胰腺上皮内瘤变（PanIN）病变和导管癌。将这种KPF小鼠模型与任何基质特异性Cre结合使用，可用于有条件地修饰感兴趣的靶基因。这将为研究基因在胰腺肿瘤微环境中不同细胞类型和多个细胞区室中的作用提供一个出色的体内工具。
