The dystroglycan receptor maintains glioma stem cells in the vascular niche

Bryan W. Day, Justin D. Lathia, Zara C. Bruce, Rochelle C.J. D’Souza, Ulrich Baumgartner, Kathleen S. Ensbey, Yi Chieh Lim, Brett W. Stringer, Seçkin Akgül, Carolin Offenhäuser, Yuchen Li, Paul R. Jamieson, Fiona M. Smith, Courtney L.R. Jurd, Thomas Robertson, Po Ling Inglis, Zarnie Lwin, Rosalind L. Jeffree, Terrance G. Johns, Krishna P.L. BhatJeremy N. Rich, Kevin P. Campbell, Andrew W. Boyd

Research output: Contribution to journalArticle

Abstract

Glioblastomas (GBMs) are malignant central nervous system (CNS) neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumourigenic glioma stem cells (GSCs) in a complex heterogeneous microenvironment. One proposed GSC niche is the extracellular matrix (ECM)-rich perivascular bed of the tumour. Here, we report that the ECM binding dystroglycan (DG) receptor is expressed and functionally glycosylated on GSCs residing in the perivascular niche. Glycosylated αDG is highly expressed and functional on the most aggressive mesenchymal-like (MES-like) GBM tumour compartment. Furthermore, we found that DG acts to maintain an MES-like state via tight control of MAPK activation. Antibody-based blockade of αDG induces robust ERK-mediated differentiation leading to reduced GSC potential. DG was shown to be required for tumour initiation in MES-like GBM, with constitutive loss significantly delaying or preventing tumourigenic potential in-vivo. These findings reveal a central role of the DG receptor, not only as a structural element, but also as a critical factor promoting MES-like GBM and the maintenance of GSCs residing in the perivascular niche.

Original languageEnglish
Pages (from-to)1033-1052
Number of pages20
JournalActa Neuropathologica
Volume138
Issue number6
DOIs
Publication statusPublished - Dec 2019
Externally publishedYes

Bibliographical note

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Keywords

  • Dystroglycan (DG)
  • EphA3
  • Glioblastoma (GBM)
  • Glioma stem cell (GSC) commitment
  • Integrin-α6
  • MAPK signalling
  • MES-like GBM
  • Perivascular niche

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  • Cite this

    Day, B. W., Lathia, J. D., Bruce, Z. C., D’Souza, R. C. J., Baumgartner, U., Ensbey, K. S., Lim, Y. C., Stringer, B. W., Akgül, S., Offenhäuser, C., Li, Y., Jamieson, P. R., Smith, F. M., Jurd, C. L. R., Robertson, T., Inglis, P. L., Lwin, Z., Jeffree, R. L., Johns, T. G., ... Boyd, A. W. (2019). The dystroglycan receptor maintains glioma stem cells in the vascular niche. Acta Neuropathologica, 138(6), 1033-1052. https://doi.org/10.1007/s00401-019-02069-x