INTERFERON REGULATORY FACTOR 1 (IRF1) LINKS IMMUNOLOGICAL AND METABOLIC TRAITS TO HISTOLOGICAL GRADE IN PANCREATIC CANCER

Pancreatic Ductal Adenocarcinoma (PDAC) is the most frequent neoplasia of the exocrine pancreas with a 5-years overall survival of less than 5% . Poor response to treatments can be attributed, at least in part, to the pervasive heterogeneity of this type of cancer, whose histological differentiation grade ranges from a well differentiated to a poorly differentiated phenotype . My lab previously dissected the transcriptional and epigenetic networks underlying PDAC grading. By using cell line models mimicking different PDAC grades, transcriptional data highlighted an interferon-related signature as peculiar of low-grade PDACs. This project aims at investigating the links between this interferon-related signature and the epithelial phenotype of well-differentiated PDACs. The role of Interferon Regulatory Factor 1 (IRF1), a transcription factor critical for the interferon response, in PDAC differentiation will be investigated. By combining a loss-of-function strategy and RNA-seq this work aimed at defining the targets and the effects of IRF1 differential expression in the mentioned cell line model. Model reliability will also be confirmed via immunohistochemistry on tumour microarrays. The immunological and metabolic phenotypes regulated by IRF1 in well differentiated PDACs will further be analysed by the use of xenografts and cell culture based assays. It will be shown that IRF1 regulates multiple interferon related genes involved in antigen processing and presentation; its deletion affects stromal composition in xenografts. IRF1 deficient cells also rewire their metabolic networks, with changes in lipid composition and metabolite usage. Overall, we found that the transcription factor IRF1 pleiotropically controls a variety of phenotypical traits of low grade PDACs: from antigen processing and presentation pathways, to metabolism, which IRF1 deficiency rewired towards an increased respiratory and lipogenic profile.