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

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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.