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

Abstract

Introduction An increasing number of recent studies suggest that tumour response to chemotherapy cannot be fully described in terms of only interaction of the drug with the main cellular target (e.g. DNA or microtubules) but can include multiple physiological and physicochemical changes. Insight into drug-induced functional alterations in cancer cells and tissues is crucially important for understanding of mechanisms of a drug action and for development new approaches to enable monitoring of the early-treatment response. Material and methods In our studies, we focus on multiparameteric analysis of tumour responses to chemotherapy using advanced fluorescence imaging techniques. Previously, we developed methodologies for in vivo probing several parameters, including cytosolic pH, metabolic status, and viscosity of plasma membrane, in mouse tumour models. Mapping of cytosolic pH in tumours is performed using ratiometric genetically encoded sensor SypHer2 and fluorescence whole-body imaging [Shirmanova et al. BBA-GS 2015]. Imaging of cellular metabolism is based on the visualisation of fluorescence intensities and lifetimes of intrinsic metabolic cofactors NAD(P)H and FAD [Shirmanova et al. Sci.Rep. 2017]. Viscosity is measured using molecular BODIPY-based rotor and fluorescence lifetime imaging microscopy (FLIM) [Shimolina et al. Sci.Rep. 2017]. Results and discussions We showed that acidification of cytosolic pH occurs after therapy with cisplatin in vivo, and this, likely, favours metabolic reorganisation of cells. Treated tumours exhibited a decreased relative contribution from free (cytosolic, protein-unbound) NAD(P)H, indicating a metabolic shift from glycolysis towards oxidative metabolism. It is interesting that optical metabolic imaging could allow early detection of tumour response to chemotherapy, before there are changes in tumour size, and metabolic changes were the same for therapeutic agents with different mechanisms of action (cisplatin, paclitaxel). Moreover, tumours treated with cisplatin displayed decreased plasma membrane viscosity. Presumably, this alteration of viscosity participates in cisplatin-induced apoptosis. Similar changes of pH, energy metabolism and viscosity were previously reported for cisplatin-treated cultured cancer cells. Conclusion These results, therefore, suggest that all investigated parameters play a role in the cytotoxicity of the drugs and may provide a useful approach for monitoring tumour responses to chemotherapy. The study was supported by the Russian Science Foundation (#14-25-00129). Introduction Pancreatic 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 epitheliallike 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. Therefor...