MODELING COHESIN-DEPENDENT ONCOGENESIS IN VITRO AND IN VIVO: POSSIBLE AMELIORATIVE EFFECTS OF PARP INHIBITION

The cohesin complex performs essential cellular functions including regulation of chromosome cohesion, chromatin 3D architecture and DNA repair. Somatic pathogenetic variants in cohesin genes have been associated with tumorigenesis but it is unclear their contribution to brain tumors. Hence, I developed in vitro and in vivo models for studying the consequences of STAG2 downregulation in cancer biology. First, in the fruit flies Drosophila melanogaster I reduced expression of the gene encoding the cohesin component SA (Stromalin, the STAG2 ortholog) and observed the consequences in terms of cell and tissue fitness. I then performed a specific reduction in clusters of larval Type II Neuroblasts of the central nervous system to assess the functional impact of SA on brain cell development. Quantitative assessment of cell differentiation markers revealed impairment of neural progenitor maturation upon SA reduction. Consistent with this, downregulated animals have a limited lifespan and a small proportion of them exhibit tumor-like masses in the brain. I also showed that Poly (ADP-ribose) polymerase (PARP) depletion or inhibition which is used to treat forms of cancer with defects in DNA repair ameliorated phenotypes of SA-deficient animals. Finally, I studied the effect of STAG2 downregulation in human in vitro models using shRNA technology in experimental settings. My data provide a model to study the role of cohesins and PARP inhibition in brain tumorigenesis and suggest that their combined impairment might cause synthetic lethality, highlighting a new tumor vulnerability.