The dystroglycan receptor maintains glioma stem cells in the vascular niche

Autor: Courtney L.R. Jurd, Kathleen S. Ensbey, Thomas Robertson, Zara C. Bruce, Paul R. Jamieson, Carolin Offenhäuser, Rochelle C.J. D’Souza, Bryan W. Day, Fiona M. Smith, Andrew W. Boyd, Po Inglis, Rosalind L. Jeffree, Kevin P. Campbell, Seckin Akgul, Yuchen Li, Justin D. Lathia, Zarnie Lwin, Yi Chieh Lim, Jeremy N. Rich, Terrance Grant Johns, Brett W. Stringer, Krishna P.L. Bhat, Ulrich Baumgartner
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
animal structures
Central nervous system
EphA3
Mice
SCID
Biology
Pathology and Forensic Medicine
Extracellular matrix
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Mice
Inbred NOD
Glioma
Glioblastoma (GBM)
Glioma stem cell (GSC) commitment
medicine
Dystroglycan
Tumor Microenvironment
Compartment (development)
Animals
Humans
Integrin-α6
Receptor
Dystroglycans
Extracellular Signal-Regulated MAP Kinases
Cells
Cultured
Original Paper
Brain Neoplasms
Dystroglycan (DG)
medicine.disease
Cell biology
030104 developmental biology
medicine.anatomical_structure
Cell Transformation
Neoplastic
MAPK signalling
biology.protein
Perivascular niche
Neoplastic Stem Cells
Female
Neurology (clinical)
Stem cell
Antibody
MES-like GBM
030217 neurology & neurosurgery
Neoplasm Transplantation
Zdroj: Acta Neuropathologica
ISSN: 1432-0533
0001-6322
Popis: 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. Electronic supplementary material The online version of this article (10.1007/s00401-019-02069-x) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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