B298: Control of cell migration in normal and neoplastic neural stem cells via a PML/EZH2-mediated regulatory loop

Deli A1,2,Valeria Amodeo1,2,Joanne Betts1,2,Stefano Bartesaghi1,2,Mikaella Vouri1,2,Rozita Roshani1,2,Sarah Oberndorfer1,2,Maya Shaked-Rabi3,David Dinsdale4,Pierluigi Nicotera5,Chris Jones6,David Michod1,2,Sebastian Brandner3,Paolo Salomoni1,2

1UCL Cancer Institute, London, UK,2Samantha Dickson Brain Cancer Unit, London, UK,3UCL Institute of Neurology, London, UK,4MRC Toxicology Unit, Leicester, UK,5DZNE, Bonn, Germany,6Institute of Cancer Research, Sutton, UK,7UCL Institute of Child Health, London, UK

Presenting date: Tuesday 3 November

Background

Control of proliferation and migration in neural progenitor/stem cells (NPCs) is essential for normal neurogenesis within the adult brain. Alterations of these processes lead to high-grade glioma (HGG). Within HGG, a subpopulation of neoplastic NPCs contributes to tumour spreading and therapy resistance. Our understanding of mechanisms underlying cell migration in normal versus neoplastic cells remains limited. Our previous work (Regad et al Nat Neurosci 2009) has shown that the stem cell factor promyelocytic leukaemia protein (PML) regulates embryonic neurogenesis via its ability to control Retinoblastoma (pRb) phosphorylation in NPCs.

Method

 

We combined in vivo and in vitro approaches, including the use of genetically modified mice, primary HGG tissues/NPCs. Our molecular work involves next generation sequencing, chromatin immunoprecipitation, use of RNA interference and bioinformatics.

Results

 

PML loss leads to a defect in cell migration during adult neurogenesis, resulting in a smaller olfactory bulb. Notably, PML promotes cell migration also in HGG NPCs. PML expression is enriched in HGG tumours belonging to the mesenchymal subtype and correlates with poor survival. Mechanistically, PML regulates a transcriptional programme involving repulsive axon guidance genes in both normal and neoplastic NPCs. This effect relies on Polycomb Repressive Complex-2-mediated repression, but it is independent on pRb.

Conclusion

Overall, these findings describe a regulatory loop shared by normal and neoplastic neural stem cells for the control of cell migration, with implications for our understanding of fundamental mechanisms controlling neurogenesis and brain cancer pathogenesis.