Background: In the biliary tree, niches of stem cells have been individuated within bile ductules and peribiliary glands. In human cholangiopathies, these niches are activated as a consequence of the bile duct inflammation and loss. In these conditions, stem cell niches are implicated in biliary regeneration but also in fibrosis and in the development of cholangiocarcinoma.
Aim: the general aim of the present project is to define the activation of stem/progenitor cell niches in human cholangiopathies, involved molecular pathways and their role in cholangiocarcinoma development.
Experimental design: The task#1 will study specific regenerative pathways in human cholangiopathies. Stem cell niches will be studied by immunohistochemistry in samples obtained from patients affected by primary biliary cholangitis, primary sclerosing cholangitis (PSC), and non anastomotic strictures. The task#2 will investigate the inter-tumoral and intra-tumoral heterogeneity in CCA by multiplex molecular analysis resolved at spatial level using Nanostring GeoMx digital spatial profiler. In task#3, the role of inflammatory pathways in the progressive carcinogenesis in PSC will be studied by molecular analysis performed with Nanostring GeoMx digital spatial profiler and immunohistochemistry.
Expected results and impact: The obtained results will allow to better characterize the involvement in biliary disease of stem cell niches within the biliary tree. Transcriptomic data obtained from CCA will lead to define tumor heterogeneity at molecular level and its association with a specific tumor cell of origin. From a therapeutic point of view, the individuation of multiple targets in CCA will help in defining personalized treatment approaches based on cellular compositions and tumor subgroup in every single patient. The results obtained in PSC-CCA will furnish a comprehensive depict of immuno-oncology of CCA developed in patients affected by PSC.
