MBRS-43. ELUCIDATING HOW NOVEL EXTRACELLULAR MATRIX SUBTYPES DIFFERENTIALLY IMPACT THE SURVIVAL OF MEDULLOBLASTOMA SUBGROUPS

Abstract

Medulloblastoma (MB) is the most common malignant paediatric brain tumour and frequently exhibits metastasis and chemoresistance. MBs are categorised into four molecular subgroups (WNT, Sonic hedgehog, Group 3 and Group 4), each associated with different demographics and clinical features. We have shown that the expression of specific extracellular matrix proteins in the brain tumour microenvironment differ between subgroups. A prime example is laminin (an ECM glycoprotein) the expression of which correlates with good overall survival in the SHH subgroup and poor overall survival in Group 4. Our aim is to determine the cause of this difference in survival. Candidate laminin-responsive-genes (LRGs) were identified using the Cavalli data set and RNA-Seq analysis of MB cells grown on 3D hydrogels with and without laminin. The role of laminin in the regulation of MMPs and the other LRG candidates was investigated by qRT-PCR, western blotting and zymography in 2D and long-term 3D-hydrogel assays. Thus far we have shown that in CHLA-01-R (metastatic Group 4 cell line) three of our LRGs are upregulated in response to laminin in 2D, as well as in preliminary 3D studies. Additionally, we have observed a unique MMP9 secretion profile of SHH cells grown in 3D compared to 2D, suggesting that our 3D assay allows us to observe relevant phenotypes absent in 2D culture. We are now in the process of identifying which of these LRG candidates are involved in metastasis and chemoresistance. This will enable the elucidation of novel therapeutic targets and crucially increase our understanding of MB-microenvironment interactions.