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. Bhat; Jeremy N. Rich; Kevin P. Campbell; Andrew W. Boyd

doi:10.1007/s00401-019-02069-x

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 journal › Article › Research › peer-review

19 Citations (Scopus)

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 language	English
Pages (from-to)	1033-1052
Number of pages	20
Journal	Acta Neuropathologica
Volume	138
Issue number	6
DOIs	https://doi.org/10.1007/s00401-019-02069-x
Publication status	Published - Dec 2019
Externally published	Yes

Keywords

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

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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

@article{8421042c281c4f1592456662c4de77f7,

title = "The dystroglycan receptor maintains glioma stem cells in the vascular niche",

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.",

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

author = "Day, {Bryan W.} and Lathia, {Justin D.} and Bruce, {Zara C.} and D{\textquoteright}Souza, {Rochelle C.J.} and Ulrich Baumgartner and Ensbey, {Kathleen S.} and Lim, {Yi Chieh} and Stringer, {Brett W.} and Se{\c c}kin Akg{\"u}l and Carolin Offenh{\"a}user and Yuchen Li and Jamieson, {Paul R.} and Smith, {Fiona M.} and Jurd, {Courtney L.R.} and Thomas Robertson and Inglis, {Po Ling} and Zarnie Lwin and Jeffree, {Rosalind L.} and Johns, {Terrance G.} and Bhat, {Krishna P.L.} and Rich, {Jeremy N.} and Campbell, {Kevin P.} and Boyd, {Andrew W.}",

note = "Funding Information: We acknowledge A/Prof Fares Al-Ejeh, QIMR Berghofer for bioinformatics support. The QIMR Berghofer flow cytometry, histology and animal facilities for their assistance and expertise in enabling us to complete this study. Funding Information: This study has been supported by NHMRC grant application I.D.1078893, Cancer Council QLD and generous donations from the Sid Faithfull Family, Cure Brain Cancer Foundation and by a Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant (1U54NS053672 to KPC). KPC is an investigator of the Howard Hughes Medical Institute. TGJ is a Principal Research Fellow with the NHMRC. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

doi = "10.1007/s00401-019-02069-x",

language = "English",

volume = "138",

pages = "1033--1052",

journal = "Acta Neuropathologica",

issn = "0001-6322",

publisher = "Springer",

number = "6",

}

Day, BW, Lathia, JD, Bruce, ZC, D’Souza, RCJ, Baumgartner, U, Ensbey, KS, Lim, YC, Stringer, BW, Akgül, S, Offenhäuser, C, Li, Y, Jamieson, PR, Smith, FM, Jurd, CLR, Robertson, T, Inglis, PL, Lwin, Z, Jeffree, RL, Johns, TG, Bhat, KPL, Rich, JN, Campbell, KP & Boyd, AW 2019, 'The dystroglycan receptor maintains glioma stem cells in the vascular niche', Acta Neuropathologica, vol. 138, no. 6, pp. 1033-1052. https://doi.org/10.1007/s00401-019-02069-x

TY - JOUR

T1 - The dystroglycan receptor maintains glioma stem cells in the vascular niche

AU - Day, Bryan W.

AU - Lathia, Justin D.

AU - Bruce, Zara C.

AU - D’Souza, Rochelle C.J.

AU - Baumgartner, Ulrich

AU - Ensbey, Kathleen S.

AU - Lim, Yi Chieh

AU - Stringer, Brett W.

AU - Akgül, Seçkin

AU - Offenhäuser, Carolin

AU - Li, Yuchen

AU - Jamieson, Paul R.

AU - Smith, Fiona M.

AU - Jurd, Courtney L.R.

AU - Robertson, Thomas

AU - Inglis, Po Ling

AU - Lwin, Zarnie

AU - Jeffree, Rosalind L.

AU - Johns, Terrance G.

AU - Bhat, Krishna P.L.

AU - Rich, Jeremy N.

AU - Campbell, Kevin P.

AU - Boyd, Andrew W.

N1 - Funding Information: We acknowledge A/Prof Fares Al-Ejeh, QIMR Berghofer for bioinformatics support. The QIMR Berghofer flow cytometry, histology and animal facilities for their assistance and expertise in enabling us to complete this study. Funding Information: This study has been supported by NHMRC grant application I.D.1078893, Cancer Council QLD and generous donations from the Sid Faithfull Family, Cure Brain Cancer Foundation and by a Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant (1U54NS053672 to KPC). KPC is an investigator of the Howard Hughes Medical Institute. TGJ is a Principal Research Fellow with the NHMRC. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12

Y1 - 2019/12

N2 - 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.

AB - 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.

KW - Dystroglycan (DG)

KW - EphA3

KW - Glioblastoma (GBM)

KW - Glioma stem cell (GSC) commitment

KW - Integrin-α6

KW - MAPK signalling

KW - MES-like GBM

KW - Perivascular niche

UR - http://www.scopus.com/inward/record.url?scp=85072055898&partnerID=8YFLogxK

U2 - 10.1007/s00401-019-02069-x

DO - 10.1007/s00401-019-02069-x

M3 - Article

C2 - 31463571

AN - SCOPUS:85072055898

SN - 0001-6322

VL - 138

SP - 1033

EP - 1052

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 6

ER -

The dystroglycan receptor maintains glioma stem cells in the vascular niche

Abstract

Keywords

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