SIX1 and SIX4 double knockout transcriptome profiling in 2D cell lines derived from murine pancreatic tumors

Pancreatic ductal adenocarcinoma is aggressive disease with a dismal five-year survival of 5%. Gene expression profiling has been instrumental for subtype classification in cancer, highlighting fundamental differences in tumors at the molecular level. Over the last years, multiple genomics studies have led to the classification of PDAC into two major subtypes: classical and basal-type. The classical subtype expresses higher levels of endodermal lineage specifiers, including HNF4A, GATA6, FOXA2, FOXA3 than the basal-type. The basal-type confers a worse prognosis, raising the possibility that loss of these lineage specifiers might enhance the malignant potential of PDAC. We found that the lineage specifier HNF4a plays a key role in maintaining a transcriptional network that characterizes the classical subtype, restraining growth in different PDAC models. Additionally, we demonstrated that HNF4a controls PDAC cell identity and proliferation, and represses the expression of SIX family members, two mesodermal lineage specifiers highly expressed in basal-type. The study was designed to compare transcriptome profiles in control versus CRISPR-mediated SIX1/4 double knockout murine pancreatic cancer cell lines.

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）是一种侵袭性极强的恶性疾病，5年生存率仅为5%，预后极差。基因表达谱分析（gene expression profiling）在肿瘤亚型分类中发挥了关键作用，可揭示肿瘤在分子层面的本质差异。近年来，多项基因组学研究已将PDAC划分为两大主要亚型：经典型与基底型（basal-type）。相较于基底型，经典型高表达一系列内胚层谱系标志物（endodermal lineage specifiers），包括HNF4A、GATA6、FOXA2及FOXA3。基底型患者的预后更差，这提示上述谱系标志物的缺失可能会增强PDAC的恶性潜能。我们的研究发现，谱系标志物HNF4α在维持经典型特征性转录网络、抑制多种PDAC模型中的肿瘤生长过程中发挥关键作用。此外，我们证实HNF4α可调控PDAC细胞的身份特征与增殖能力，并抑制SIX家族成员的表达——这两类中胚层谱系标志物（mesodermal lineage specifiers）在基底型肿瘤中呈高表达水平。本研究旨在对比对照组与CRISPR介导的SIX1/4双敲除小鼠胰腺癌细胞系的转录组谱（transcriptome profiles）特征。