Oncostatin M as pro-inflammatory cytokine modulating intrahepatic cholangiocarcinoma progression and tumor-stroma interaction - 2022PNZ9KP

This project aims to: i) mechanistically investigate the involvement of OSM in biological responses of iCCA cells, related to tumor progression, including cell proliferation and motility, epithelial mesenchymal transition (EMT) and angiogenesis. In this connection, we will employ in vitro experiments and an in vivo orthotopic mouse model; ii) explore the role of OSM in the cross-talk between macrophages and iCCA cells as well as human hepatic stellate cells (HSCs, which represent along with portal myofibroblasts the main source of CAFs) and iCCA cells, by employing 3D scaffolds; iii) evaluate OSM expression and OSM-related genes and mediators in iCCA tumor specimens taking advantage of Hyperion imaging system and outline their significance in relation to clinical parameters; iv) determine OSM expression and OSM pathways in liquid biopsies of healthy subjects and iCCA patients. With this project we expect to disclose the role of OSM in: a) affecting tumor-stroma interaction; b) modulating tumor infiltrating immune cells; c) favoring CSCs and chemo-resistance and to define the prognostic significance of OSM or OSM-related genes/mediators/pathways as putative markers for iCCA. Moreover, we expect to underline the impact of targeting OSM in improving current therapeutic strategies for iCCA development and progression. Due to the increasing incidence worldwide of iCCA and the lack of effective therapies for this aggressive tumor diagnosed in advanced clinical stage, the data generated by this project will respond to the urgent need for reliable biomarkers and putative novel therapeutic targets to both predict and interfere with iCCA development and progression.