The dystroglycan receptor maintains glioma stem cells in the vascular niche.
Animals
Brain Neoplasms
/ blood supply
Cell Transformation, Neoplastic
Cells, Cultured
Dystroglycans
/ metabolism
Extracellular Signal-Regulated MAP Kinases
/ metabolism
Female
Glioma
/ blood supply
Humans
Mice, Inbred NOD
Mice, SCID
Neoplasm Transplantation
Neoplastic Stem Cells
/ metabolism
Tumor Microenvironment
/ physiology
Dystroglycan (DG)
EphA3
Glioblastoma (GBM)
Glioma stem cell (GSC) commitment
Integrin-α6
MAPK signalling
MES-like GBM
Perivascular niche
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
09
05
2019
accepted:
22
08
2019
revised:
21
08
2019
pubmed:
30
8
2019
medline:
4
9
2020
entrez:
30
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31463571
doi: 10.1007/s00401-019-02069-x
pii: 10.1007/s00401-019-02069-x
pmc: PMC6851226
doi:
Substances chimiques
Dystroglycans
146888-27-9
Extracellular Signal-Regulated MAP Kinases
EC 2.7.11.24
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1033-1052Subventions
Organisme : National Health and Medical Research Council (NHMRC) - Australia
ID : I.D.1078893
Pays : International
Organisme : Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
ID : 1U54NS053672
Pays : International
Références
J Neurooncol. 2011 Nov;105(2):261-73
pubmed: 21512826
EBioMedicine. 2015 Aug 15;2(10):1351-63
pubmed: 26629530
Lab Invest. 2010 Nov;90(11):1645-60
pubmed: 20714324
Cell. 1998 Dec 11;95(6):859-70
pubmed: 9865703
Development. 1999 May;126(10):2033-44
pubmed: 10207129
Mol Biol Cell. 2003 May;14(5):2088-103
pubmed: 12802077
Cell. 1991 Sep 20;66(6):1121-31
pubmed: 1913804
Cancer Res. 2018 Sep 1;78(17):5023-5037
pubmed: 29945963
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Mol Cell Biol Hum Dis Ser. 1993;3:139-66
pubmed: 8111538
J Biol Chem. 2013 Jan 25;288(4):2132-42
pubmed: 23223448
Cancer Res. 2012 May 15;72(10):2578-88
pubmed: 22589276
Cancer Cell. 2010 Jan 19;17(1):98-110
pubmed: 20129251
Dev Cell. 2016 Sep 12;38(5):548-66
pubmed: 27569418
Cell Stem Cell. 2010 May 7;6(5):421-32
pubmed: 20452317
Eur J Neurosci. 2011 Jun;33(12):2179-86
pubmed: 21501259
Cancer Cell. 2017 Jul 10;32(1):42-56.e6
pubmed: 28697342
EMBO Rep. 2004 May;5(5):484-9
pubmed: 15071496
J Neuropathol Exp Neurol. 2012 Dec;71(12):1047-63
pubmed: 23147502
Mol Biol Cell. 2012 Mar;23(5):771-80
pubmed: 22238358
Cancer Cell. 2013 Feb 11;23(2):238-48
pubmed: 23410976
Cancer Res. 2014 Aug 15;74(16):4470-81
pubmed: 25125683
Cancer Cell. 2007 Jan;11(1):69-82
pubmed: 17222791
Brain Pathol. 2012 Sep;22(5):670-6
pubmed: 22288519
Cell Rep. 2014 May 8;7(3):747-61
pubmed: 24767994
PLoS One. 2009 Nov 13;4(11):e7752
pubmed: 19915670
Nature. 1990 May 24;345(6273):315-9
pubmed: 2188135
Mol Cancer. 2018 Feb 19;17(1):44
pubmed: 29455644
Cell Stem Cell. 2009 Jun 5;4(6):568-80
pubmed: 19497285
Am J Pathol. 2003 Mar;162(3):849-60
pubmed: 12598319
Cell Tissue Res. 2012 Feb;347(2):429-41
pubmed: 22307776
J Neuropathol Exp Neurol. 1995 Sep;54(5):651-6
pubmed: 7666053
Eur J Cancer. 2004 Sep;40(14):2143-51
pubmed: 15341990
Sci STKE. 2001 Dec 11;2001(112):re20
pubmed: 11741094
Cancers (Basel). 2018 Dec 17;10(12):null
pubmed: 30562956
Nat Rev Cancer. 2010 Mar;10(3):165-80
pubmed: 20179713
Brain Res. 2013 Mar 29;1503:89-96
pubmed: 23395731
Cancer Cell. 2013 Sep 9;24(3):331-46
pubmed: 23993863
Cancer Res. 2006 Aug 15;66(16):7843-8
pubmed: 16912155
Nature. 2002 Jul 25;418(6896):422-5
pubmed: 12140559
Nature. 2002 Jul 25;418(6896):417-22
pubmed: 12140558
Cell. 1995 Jan 27;80(2):179-85
pubmed: 7834738
Cancers (Basel). 2013 Apr 03;5(2):357-71
pubmed: 24216981
Sci Rep. 2019 Mar 20;9(1):4902
pubmed: 30894629
Cell. 2013 Mar 28;153(1):139-52
pubmed: 23540695
J Biol Chem. 1998 Mar 6;273(10):5903-7
pubmed: 9488728
Cell. 2019 Aug 8;178(4):835-849.e21
pubmed: 31327527
Cancer Res. 2014 Jan 15;74(2):412-9
pubmed: 24408923
Development. 2007 May;134(9):1723-36
pubmed: 17395644
J Neurosci. 2014 Nov 12;34(46):15260-80
pubmed: 25392494
BMC Neurosci. 2017 Aug 14;18(1):63
pubmed: 28806929
Nat Rev Cancer. 2007 Oct;7(10):733-6
pubmed: 17882276
Nature. 1992 Feb 20;355(6362):696-702
pubmed: 1741056
Oncotarget. 2016 Sep 13;7(37):59860-59876
pubmed: 27494882
Acta Neuropathol. 1989;79(3):305-9
pubmed: 2609937
J Neurochem. 2012 Mar;120(6):928-47
pubmed: 22117643
Cancer Biol Ther. 2006 Apr;5(4):441-8
pubmed: 16575202
Acta Neuropathol. 2016 Jun;131(6):803-20
pubmed: 27157931
FEBS Lett. 2006 Jun 12;580(14):3381-5
pubmed: 16709410
Curr Opin Cell Biol. 1993 Feb;5(1):82-7
pubmed: 8448034
J Neurochem. 2015 Nov;135(3):522-38
pubmed: 26171643
J Biol Chem. 2009 Apr 24;284(17):11279-84
pubmed: 19244252
Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3290-4
pubmed: 1373493