Interferon regulatory factor 1 (IRF1) controls the metabolic programmes of low-grade pancreatic cancer cells (ChIP-Seq)

Pancreatic ductal adenocarcinomas (PDACs) are composed of a mixture of highly heterogeneous cancer cells with distinct gene expression programs and functional properties, ranging from well-differentiated (low-grade) epithelial cells forming pseudo-glandular structures, to undifferentiated (high-grade) quasi-mesenchymal cells. Low-grade, differentiated PDAC cells are characterized by the constitutive expression of many Interferon (IFN)-stimulated genes (ISGs) but the mechanistic bases and the functional implications of this property are unknown. Here we show that constitutive ISG expression as well as responsiveness to IFN stimulation depend on the maintenance of high expression levels of the transcription factor IRF1 (Interferon Regulatory Factor 1) by epithelial lineage-determining transcription factors. IRF1-dependent gene expression provides differentiated PDAC cells with a range of distinctive properties related to antigen presentation and processing and maintenance of epithelial identity, as well as a distinctive metabolic program in which both mitochondrial respiration and fatty acid synthesis are directly suppressed Chromatin from human pancreatic ductal adenocarcinoma cell lines was immunoprecipitated with various transcription factors and histone modification targeting antibodies and subjected to multiparallel sequencing. Experiments were carried out in unmodified and genome edited clonal CFPAC1 cells.