In vivo characterization of CUX1 in tumorigenesis and tumor progression in pancreatic cancer

以前，我们确定了转录因子CUX 1作为胰腺癌肿瘤进展，转移和耐凋亡的重要介质。此外，我们表征了几个调节其对侵袭和存活的影响的CUX 1靶基因。我们可以证明，通过生存途径上调CUX 1导致对化疗药物的耐药性增强。本项目旨在通过我们最近建立的Cux 1条件性基因敲入小鼠模型来研究Cux 1在体内致癌、肿瘤进展和耐药性方面的作用。该小鼠模型将与胰腺前体病变（LSL-KrasG 12 D; Pdx 1-Cre; KC-小鼠）和侵袭性胰腺癌（LSL-KrasG 12 D; LSL-p53 R172 H; Pdx 1-Cre; KPC-小鼠）的已建立条件小鼠模型杂交。该项目将研究Cux 1在激活的K-Ras背景下是否会导致侵袭性癌症的发展或能够促进肿瘤进展。此外，我们将研究Cux 1对化疗药物（如吉西他滨）治疗后药物诱导的细胞凋亡的耐药性的影响。通过使用全基因组转录组分析，将确定并单独表征调节细胞分化、肿瘤发生和进展的Cux 1依赖性靶基因。

Previously, we identified the transcription factor CUX1 as important mediator of tumor progression, metastasis and resistance to apoptosis in pancreatic cancer. Furthermore, we characterized several CUX1 target genes modulating its effects on invasion and survival. We could show that upregulation of CUX1 by survival pathways leads to enhanced resistance against chemotherapeutic drugs. This project aims to investigate the effect of Cux1 on carcinogenesis, tumor progression and drug resistance in vivo by characterization of a conditional knock-in mouse model of Cux1 which we generated recently. This mouse model will be crossed with established conditional mouse models of pancreatic precursor lesions (LSL-KrasG12D; Pdx1-Cre; KC-mouse) and invasive pancreatic cancer (LSL-KrasG12D; LSL-p53R172H; Pdx1-Cre; KPC-mouse). The project will examine if Cux1 in the context of activated K-Ras leads to the development of invasive cancers or is able to enhance tumor progression. In addition, we will investigate the impact of Cux1 on resistance to drug-induced apoptosis after treatment with chemotherapeutic drugs such as gemcitabine. By using genome-wide transcriptome profiling, Cux1-dependent target genes modulating cell differentiation, tumorigenesis and progression will be identified and individually characterized.