Human Genetics Laboratory- DBSV - VARESE, ITALY

1) Functional characterization of the role played by the RNASET2 tumor suppressor gene in the control of tumor progression in various cancer types. Over the past 20 years, the human genetics research group has generated numerous experimental data, using both in vitro and in vivo experimental models, supporting the role of the human RNASET2 as a pleiotropic tumor suppressor gene in various cancer types, such as ovarian cancer, melanoma, prostate cancer and pancreatic cancer. Of particular interest has been the identification of a "non-cell-autonomous" antitumor mechanism mediated by the interaction of the extracellular protein RNASET2 with a key component of the tumor microenvironment, represented by cells of the monocyte-macrophage lineage. Recent studies have highlighted the ability of the RNASET2 protein to act as an "alarmin", stimulating the recruitment of monocytes/macrophages within the tumor mass and above all inducing a phenotypic "switch" in these cells from the M2 (pro-tumor) to the M1 (anti-tumor) polarization state. In parallel, numerous studies in in vitro experimental systems have defined a cell-autonomous mode of tumor suppression mediated by the RNASET2 gene, based on the coordinated control of several cancer-related cellular parameters, such as cell proliferation, apoptosis, cell adhesion/migration rate, and cytoskeletal organization. 2) More recently, the human genetics research group started a second line of research aimed at defining the role of the RNASET2 gene in the pathogenesis of Aicardi-Goutières syndrome (AGS), an autosomal recessive Mendelian pediatric leukoencephalopathy. Specifically, functional studies in in vitro cellular models of an allelic series representing several mutations with probable loss-of-function effects found in independent AGS patients are underway.