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3D hydrogels reveal medulloblastoma subgroup differences and identify extracellular matrix subtypes that predict patient outcome

Linke, Franziska; Aldighieri, Macha; Lourdusamy, Anbarasu; Grabowska, Anna M.; Stolnik, Snow; Kerr, Ian D.; Merry, Catherine LR; Coyle, Beth

3D hydrogels reveal medulloblastoma subgroup differences and identify extracellular matrix subtypes that predict patient outcome Thumbnail


Authors

Franziska Linke

Macha Aldighieri

Anbarasu Lourdusamy

Anna M. Grabowska

Snow Stolnik



Abstract

© 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. Medulloblastoma (MB) is the most common malignant brain tumour in children and is subdivided into four subgroups: WNT, SHH, Group 3, and Group 4. These molecular subgroups differ in their metastasis patterns and related prognosis rates. Conventional 2D cell culture methods fail to recapitulate these clinical differences. Realistic 3D models of the cerebellum are therefore necessary to investigate subgroup-specific functional differences and their role in metastasis and chemoresistance. A major component of the brain extracellular matrix (ECM) is the glycosaminoglycan hyaluronan. MB cell lines encapsulated in hyaluronan hydrogels grew as tumour nodules, with Group 3 and Group 4 cell lines displaying clinically characteristic laminar metastatic patterns and levels of chemoresistance. The glycoproteins, laminin and vitronectin, were identified as subgroup-specific, tumour-secreted ECM factors. Gels of higher complexity, formed by incorporation of laminin or vitronectin, revealed subgroup-specific adhesion and growth patterns closely mimicking clinical phenotypes. ECM subtypes, defined by relative levels of laminin and vitronectin expression in patient tissue microarrays and gene expression data sets, were able to identify novel high-risk MB patient subgroups and predict overall survival. Our hyaluronan model system has therefore allowed us to functionally characterize the interaction between different MB subtypes and their environment. It highlights the prognostic and pathological role of specific ECM factors and enables preclinical development of subgroup-specific therapies. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Citation

Linke, F., Aldighieri, M., Lourdusamy, A., Grabowska, A. M., Stolnik, S., Kerr, I. D., Merry, C. L., & Coyle, B. (2021). 3D hydrogels reveal medulloblastoma subgroup differences and identify extracellular matrix subtypes that predict patient outcome. Journal of Pathology, 253(3), 326-338. https://doi.org/10.1002/path.5591

Journal Article Type Article
Acceptance Date Nov 10, 2020
Online Publication Date Nov 18, 2020
Publication Date 2021-03
Deposit Date Dec 18, 2020
Publicly Available Date Dec 18, 2020
Journal Journal of Pathology
Print ISSN 0022-3417
Electronic ISSN 1096-9896
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 253
Issue 3
Pages 326-338
DOI https://doi.org/10.1002/path.5591
Keywords Medulloblastoma, Laminin, Vitronectin, Subtypes, Hydrogel, ECM, Metastasis, Chemoresistance, 3D model
Public URL https://nottingham-repository.worktribe.com/output/5156059
Publisher URL https://onlinelibrary.wiley.com/doi/10.1002/path.5591

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