Abstract
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.
Highlights
Medulloblastoma (MB) is the most common malignant brain tumour in children and is subdivided into four subgroups: WNT, sonic hedgehog (SHH), Group 3, and Group 4
Based on the RNA and protein expression levels of MB subgroup-specific extracellular matrix (ECM) components and receptors, we identified the glycoproteins laminin and vitronectin as functional markers that can act as predictors of a laminar or nodular phenotype
To study growth differences between MB subgroups and the role of the ECM, we compared long-term growth of MB cell lines encapsulated in hyaluronan hydrogels with conventional 2D cell culture
Summary
Medulloblastoma (MB) is the most common malignant brain tumour in children and is subdivided into four subgroups: WNT, sonic hedgehog (SHH), Group 3, and Group 4 These molecular subgroups are characterized by different metastasis patterns and related prognosis rates [1,2,3,4]. In metastatic MB, Group 3 primary tumours are usually significantly smaller than SHH or Group 4 tumours; they hypothesized that an earlier dissemination event might be a characteristic of Group 3 tumours. They categorized the type of metastasis and found that Group 3 tumours predominantly spread as nodules and a thin laminar coating (laminar phenotype). The majority of genomic and transcriptional alterations that have been identified to date have, not been linked to signalling aberrations that could explain leptomeningeal spread or be targeted in metastatic MB subgroups [14]
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