A PML/Slit Axis Controls Physiological Cell Migration and Cancer Invasion in the CNS

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Valeria Amodeo, Deli A, Joanne Betts, Stefano Bartesaghi, Ying Zhang, Angela Richard-Londt, Matthew Ellis, Rozita Roshani, Mikaella Vouri, Sara Galavotti, Sarah Oberndorfer, Ana Paula Leite, Alan Mackay, Aikaterini Lampada, Eva Wessel Stratford, Ningning Li, David Dinsdale, David Grimwade, Chris Jones, Pierluigi Nicotera, David Michod, Sebastian Brandner, Paolo Salomoni
Cell migration through the brain parenchyma underpins neurogenesis and glioblastoma (GBM) development. Since GBM cells and neuroblasts use the same migratory routes, mechanisms underlying migration during neurogenesis and brain cancer pathogenesis may be similar. Here, we identify a common pathway controlling cell migration in normal and neoplastic cells in the CNS. The nuclear scaffold protein promyelocytic leukemia (PML), a regulator of forebrain development, promotes neural progenitor/stem cell (NPC) and neuroblast migration in the adult mouse brain. The PML pro-migratory role is active also in transformed mouse NPCs and in human primary GBM cells. In both normal and neoplastic settings, PML controls cell migration via Polycomb repressive complex 2 (PRC2)-mediated repression of Slits, key regulators of axon guidance. Finally, a PML/SLIT1 axis regulates sensitivity to the PML-targeting drug arsenic trioxide in primary GBM cells. Taken together, these findings uncover a drug-targetable molecular axis controlling cell migration in both normal and neoplastic cells.

Graphical abstract

Teaser

Amodeo et al. find that the growth suppressor PML regulates cell migration during adult neurogenesis and neoplastic transformation via PRC2-mediated repression of Slit genes. Changes in Slit transcription upon PML loss are caused by global reduction of the repressive H3K27me3 histone mark and are associated with its redistribution to nuclear lamina.


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