HUMAN AND MOLECULAR GENETICS LABORATORIES - DBSV

The Human Genetics and Molecular Genetics laboratories carry out research activities in genetics and molecular biology aimed at investigating the genetic and molecular bases of selected human cancers and Mendelian disorders, with particular emphasis on the human genes RNASET2 and PRODH, as well as on specific microRNAs. These projects share a common experimental approach, focusing on functional studies at the genetic, genomic, phenotypic, biochemical, and cellular biology levels, with the goal of understanding how the genes under investigation may be exploited as biomarkers or therapeutic targets. With regard to RNASET2, these studies—conducted using a wide range of in vitro and in vivo experimental models—have allowed us to define RNASET2 as a highly pleiotropic tumor suppressor gene, capable of inhibiting tumor growth through both cell-autonomous and non–cell-autonomous mechanisms. The latter have been shown to depend on the establishment of cross-talk within the tumor microenvironment (TME), whereby key TME components, such as cells of the monocyte–macrophage lineage, are functionally involved in RNASET2-mediated tumor suppression. More recently, a second line of research has been initiated based on genetic evidence supporting a role for RNASET2 in the pathogenesis of Aicardi–Goutières syndrome, a rare pediatric Mendelian leukodystrophy with autosomal recessive inheritance. The PRODH gene encodes proline dehydrogenase, a key enzyme in proline catabolism, and is implicated in both Mendelian genetic disorders, such as type I hyperprolinemia, and complex diseases, including schizophrenia and cancer. In particular, we are investigating its role in lung adenocarcinoma, where PRODH expression appears to be associated with a favorable prognosis at early disease stages. At the mechanistic level, we have demonstrated that PRODH is involved in the induction of cellular senescence. While this process leads to cell cycle arrest in tumor cells, it also promotes the production of inflammatory cytokines capable of remodeling the tumor microenvironment, thereby favoring the recruitment of innate immune cells and endothelial cells. Finally, we are quantifying specific circulating microRNAs with the aim of developing a screening test for non–small cell lung cancer, through the application of digital PCR, which enables absolute quantification of target molecules.