Department of Cell and Molecular Biology, Sid Faithfull Brain Cancer Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Faculty of Health, Queensland University of Technology, Brisbane, 4059, Australia.
Acta Neuropathol. 2019 Dec;138(6):1033-1052. doi: 10.1007/s00401-019-02069-x. Epub 2019 Aug 28.
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.
胶质母细胞瘤（GBMs）是一种恶性中枢神经系统（CNS）肿瘤，预后非常差。它们显示出细胞层次结构，包含在复杂异质微环境中自我更新的肿瘤发生神经胶质瘤干细胞（GSCs）。一个被提议的 GSC 生态位是肿瘤富含细胞外基质（ECM）的血管周床。在这里，我们报告说，位于血管周生态位的 GSCs 上表达并具有功能性糖基化的 ECM 结合抗肌营养不良糖蛋白（DG）受体。糖基化的αDG 在最具侵袭性的间充质样（MES 样）GBM 肿瘤区室中高度表达和功能。此外，我们发现 DG 通过严格控制 MAPK 激活来维持 MES 样状态。基于抗体的 αDG 阻断诱导强大的 ERK 介导的分化，导致 GSC 潜力降低。DG 被证明是 MES 样 GBM 起始所必需的，其组成性缺失显着延迟或防止体内致瘤潜能。这些发现揭示了 DG 受体的核心作用，不仅作为结构元件，而且作为促进 MES 样 GBM 和驻留在血管周生态位中的 GSCs 维持的关键因素。
