PP07. A PML/POLYCOMB/SLIT AXIS REGULATES MIGRATION OF BOTH NORMAL AND NEOPLASTIC CELLS IN THE CNS

Abstract

INTRODUCTION: The control of SVZ neural progenitor/stem cells (NPCs) migration through the rostral migratory stream (RMS) is essential for normal neurogenesis and serve as the fundamental basis of production/replacement of neurons in the adult brain. Alterations of these processes can lead to neoplastic transformation and glioblastoma multiforme (GBM). The ability of GBM cells to migrate through the brain parenchyma represents a key factor underlying GBM aggressiveness. GBM cells use the same routes used by neuroblasts/immature neurons and neural stem cells upon injury, such as vessels and myelin tracts, suggesting that GBM migration may lay its roots in essential cellular processes controlling migration of immature neurons/neuroblasts and neural stem cells (1). However, our understanding of mechanisms regulating cell migration/invasion during brain tumourigenesis remains limited. METHODS: We combined in vivo and in vitro approaches, including the use of genetically modified mice, primary HGG tissues/NPCs (in collaboration with S Brandner, UCL, C Jones, ICR, S Pollard, Edinburgh, and others). RESULTS: Here we report that the stem cell factor and RAS effector Promyelocytic Leukaemia protein (PML) (2,3) regulates cell migration through the epigenetic control of Slit axon guidance genes in normal and neoplastic cells in the central nervous system. Loss of PML leads to impaired NSC and neuroblast migration and a smaller olfactory bulb in the adult mouse brain. PML controls cell migration via Polycomb Repressive 2-dependent regulation of the Slit axon guidance genes. A similar epigenetically controlled PML/Slit axis is functional also upon RAS-driven neoplastic transformation of NSCs and in primary GBM cells. PML expression inversely correlates with Slit1 expression and patient prognosis in GBM and is enriched in the mesenchymal subtype, which is characterized by activation of the RAS/MAPK pathway. Finally, PML loss impairs tumor growth in an orthotopic animal model. CONCLUSIONS: Taken together, these findings disclose a novel molecular axis at the root of cell migration during normal neurogenesis and brain tumourigenesis. Reference 1. Cuddapah VA et al. Nat Rev Neurosci 15: 455–465. 2. Regad T. et al. Nature neuroscience 12: 132–140. 3. Salomoni P. et al. Cell Res 18: 622–640.