OP40: CONTROL OF MIGRATION IN NORMAL AND GLIOMA NEURAL STEM CELLS BY THE STEM CELL FACTOR PROMYELOCYTIC LEUKAEMIA PROTEIN (PML)

INTRODUCTION: Control of cell cycle and migration in neural progenitor/stem cells (NPCs) is essential for normal neurogenesis within the adult brain. Alteration of these processes leads to high-grade glioma (HGG). Tumour spreading and the presence of neoplastic NPCs are key factors underlying HGG aggressiveness and resistance to treatment. Our understanding of mechanisms regulating cell migration/invasion during brain tumourigenesis remains limited. Our previous work (Regad et al Nat Neurosci 2009) showed that the stem cell factor promyelocytic leukaemia protein (PML) regulates embryonic neurogenesis. In normal cells, PML acts as tumour suppressor upon oncogenic RAS activation via its ability to control p53 and pRb. PML is targetable pharmacologically via treatment with arsenic trioxide. METHOD: 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: PML loss leads to increased adult NPC proliferation but on the other hand it causes a cell autonomous defect in cell migration, resulting in a smaller olfactory bulb. Notably, PML expression is enriched in HGG tumours belonging to the mesenchymal subtype (characterised by RAS/MAPK activation) and correlates with poor survival. Mechanistically, PML is downstream RAS signalling and positively regulates migration/invasion through the control of a transcriptional programme involving key axon guidance and migration genes in both normal and HGG NPCs. CONCLUSION: Overall, these findings reveal a concept whereby a tumour suppressor may bear tumour-promoting functions in HGG through the control of migration/invasion.