PO-324 Interferon regulatory factor 1 (IRF1) regulates inflammatory and metabolic phenotypes in pancreatic ductal adenocarcinoma

Abstract

IntroductionPancreatic Ductal Adenocarcinoma (PDAC) is the most frequent neoplasia of the exocrine pancreas. This tumour is and is characterised by a pervasive heterogeneity, with the coexistence of a range of histological grades, from epithelial-like to mesenchymal-like features. We previously dissected the transcriptional and epigenetic networks underlying PDAC grading. We identified the association of low grade phenotypes with a cell-autonomous interferon-related signature. Therefore, we set out to investigate the sustainment of inflammatory and interferon-related signatures in well-differentiated pancreatic cancer cells, and to determine the role of this network in PDAC biology.Material and methodsWe used cell-line based models of cancer differentiation, xenografts and human samples. We used CRISPR-Cas9 mediated genome editing to delete the transcription factor IRF1 (Interferon Regulatory Factor 1) in low-grade PDAC cells. RNA-seq, metabolic assays (oxygraphy, steady state metabolomics, fluxomics) and cell biology assays were carried out in IRF1 wt and knock-out cell lines. Data validation in human PDAC samples was carried out by immunohistochemistry.Results and discussionsWe found that IRF1 is a transcription factor differentially expressed between low- and high-grade PDACs, both in cell lines and in human tumours. IRF1 deletion in low-grade cell lines reduced the expression of genes in the antigen processing and presentation pathways, while its overexpression promoted the expression of the same genes in high-grade cells, where they are normally not expressed. Furthermore, xenografted IRF1-deficient cell lines recruited fewer immune cells in vivo. IRF1 deletion also affected epithelial phenotypes, including growth rate, cell shape, motility and collagen remodelling ability. Alongside, we unveiled a role of IRF1 in the control of the metabolism of low-grade PDAC cells, consisting in the control of mitochondrial respiration and lipogenesis as well as of the overall lipid profile of these cells.ConclusionTo conclude, our results provide hints on the regulatory networks controlling cell differentiation in human PDACs. We show that IRF1 acts as a pleiotropic regulator in the low grade component of PDACs, with wide effects on immunological and metabolic features of this cancer population. Our work reinforces the body of knowledge needed for the development of those therapeutic strategies aiming at exploiting immunological or metabolic pitfalls.