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A PML/Slit axis controls physiological cell migration and cancer invasion in the CNS

A PML/Slit axis controls physiological cell migration and cancer invasion in the CNS
A PML/Slit axis controls physiological cell migration and cancer invasion in the CNS
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.
2211-1247
411-426
Amodeo, Valeria
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A, Deli
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Betts, Joanne
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Bartesaghi, Stefano
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Zhang, Ying
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Richard-Loendt, Angela
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Ellis, Matthew
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Roshani, Rozita
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Vouri, Mikaela
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Galavotti, Sara
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Oberndorfer, Sarah
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Leite, Ana Paula
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Mackay, Alan
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Lampada, Aikaterini
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Stratford, Eva Wessel
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Li, Ning Ning
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Dinsdale, David
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Grimwade, David
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Jones, Chris
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Nicotera, Pierluigi
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Michod, David
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Brandner, Sebastian
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Salomoni, Paolo
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Amodeo, Valeria
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A, Deli
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Betts, Joanne
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Bartesaghi, Stefano
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Zhang, Ying
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Richard-Loendt, Angela
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Ellis, Matthew
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Roshani, Rozita
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Vouri, Mikaela
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Galavotti, Sara
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Oberndorfer, Sarah
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Leite, Ana Paula
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Mackay, Alan
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Lampada, Aikaterini
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Stratford, Eva Wessel
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Li, Ning Ning
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Dinsdale, David
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Grimwade, David
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Jones, Chris
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Nicotera, Pierluigi
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Michod, David
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Brandner, Sebastian
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Salomoni, Paolo
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Amodeo, Valeria, A, Deli, Betts, Joanne, Bartesaghi, Stefano, Zhang, Ying, Richard-Loendt, Angela, Ellis, Matthew, Roshani, Rozita, Vouri, Mikaela, Galavotti, Sara, Oberndorfer, Sarah, Leite, Ana Paula, Mackay, Alan, Lampada, Aikaterini, Stratford, Eva Wessel, Li, Ning Ning, Dinsdale, David, Grimwade, David, Jones, Chris, Nicotera, Pierluigi, Michod, David, Brandner, Sebastian and Salomoni, Paolo (2017) A PML/Slit axis controls physiological cell migration and cancer invasion in the CNS. Cell Reports, 20 (2), 411-426. (doi:10.1016/j.celrep.2017.06.047).

Record type: Article

Abstract

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.

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Accepted/In Press date: 19 June 2017
Published date: 11 July 2017

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Local EPrints ID: 427469
URI: https://eprints.soton.ac.uk/id/eprint/427469
ISSN: 2211-1247
PURE UUID: 1041d9e6-68ac-4b2a-994d-f7062845e7fb

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Date deposited: 17 Jan 2019 17:30
Last modified: 14 Aug 2019 16:36

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Contributors

Author: Valeria Amodeo
Author: Deli A
Author: Joanne Betts
Author: Stefano Bartesaghi
Author: Ying Zhang
Author: Angela Richard-Loendt
Author: Matthew Ellis
Author: Rozita Roshani
Author: Mikaela Vouri
Author: Sara Galavotti
Author: Sarah Oberndorfer
Author: Ana Paula Leite
Author: Alan Mackay
Author: Aikaterini Lampada
Author: Eva Wessel Stratford
Author: Ning Ning Li
Author: David Dinsdale
Author: David Grimwade
Author: Chris Jones
Author: Pierluigi Nicotera
Author: David Michod
Author: Sebastian Brandner
Author: Paolo Salomoni

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