P01.07 The Dystroglycan Complex Promotes Mesenchymal-Like Glioblastoma through Interaction with EphA Receptor Tyrosine Kinases
| Autor: | J. D. Lathia, Zara C. Bruce, Fares Al-Ejeh, Jeremy N. Rich, Andrew W. Boyd, Bryan W. Day, Brett W. Stringer, Kevin P. Campbell, Thomas Robertson, Kathleen S. Ensbey |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Cancer Research
Glycosylation biology Receptor Protein-Tyrosine Kinases Mesenchymal stem cell medicine.disease Phenotype Receptor tyrosine kinase Epithelium Dystroglycan complex chemistry.chemical_compound medicine.anatomical_structure Oncology chemistry Glioma Cancer research medicine biology.protein Neurology (clinical) POSTER PRESENTATIONS |
| Popis: | Glioblastomas (GBMs) are the most common and malignant CNS neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs) in a highly vascular complex microenvironment. One proposed niche for GSCs is the perivascular environment or vascular bed of the tumor, where these cells have the potential to undergo mesenchymal differentiation. Extracellular matrix (ECM) proteins and basement membrane formation are key structural components of this niche and regulate normal stem cell and tumor proliferation. Dystroglycan (DG) is a receptor that mediates laminin binding and is highly glycosylated. DG is comprised of a transmembrane β-subunit (βDG) and a cell-surface α-subunit (αDG), a G-like domain on laminin binds to a glycan structure on αDG and this interaction plays a critical role in assembling ECM proteins in many epithelial tissues, including the brain. Eph receptor tyrosine kinases are implicated in tissue boundary formation during development and mediate cell migration through regulation of repulsive and adhesive guidance cues. More recently the Eph family have been shown to be functionally over expressed in a wide variety of human cancers. Our previous findings found that EphA3 is highly expressed on GSCs particularly around blood vessels and act in a kinase independent manner to maintain a mesenchymal phenotype promoting glioma tumorigenesis. Moreover, EphA3 has been shown to be over expressed and functional on mesenchymal stromal cells in a number of human cancers, and EphA3 antibody targeting inhibited tumor growth by disrupting newly formed tumor microvasculature. We have generated compelling data showing that αDG is one of the central mediators regulating attachment to ECM proteins within the GBM vascular niche and is responsible for driving a mesenchymal phenotype by direct interaction with EphA3. αDG is co-expressed with EphA3 and integrin α6. Knockdown of DG induces differentiation and reduces intracranial tumor formation increasing overall survival in mesenchymal subtype GBM animal models. Furthermore, we show that an αDG antibody, which specifically binds to αDG glycosylation sites preventing laminin binding, induces a potent anti-proliferative and differentiation response irrespective of GBM molecular subtype. These data identify αDG as a driver of mesenchymal GBM and validate αDG a potential GSC therapeutic target. |
| Databáze: | OpenAIRE |
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