Brevican knockdown reduces late-stage glioma tumor aggressiveness

Abstract

Growing evidence supports the important role of the tumor microenvironment (TME) in cancer biology. A defining aspect of the glioma TME is the unique composition and structure of its extracellular matrix (ECM), which enables tumor cells to overcome the inhibitory barriers of the adult central nervous system (CNS). In this way, the TME plays a role in glioma invasion and the cellular heterogeneity that distinguishes these tumors. Brain Enriched Hyaluronan Binding (BEHAB)/brevican (B/b), is a CNS-specific ECM constituent and is upregulated in the glioma TME. Previous studies have shown B/b exerts a pro-invasive function, suggesting it may represent a target to reduce glioma pathogenesis. Herein, we also provide evidence that B/b expression is enriched in the glioma initiating cell (GIC) niche. We demonstrate B/b plays roles in the pathological progression, aggressiveness, and lethality of tumors derived from human GICs and traditional glioma cell lines. Interestingly, we found that B/b is not required to maintain the defining phenotypic properties of GICs and thereby acts primarily in late stages of glioma progression. This study suggests that the increased expression of B/b in the TME is a valuable therapeutic target for glioma.

Pan-cancer transcriptomic analysis associates long non-coding RNAs with key mutational driver events

“…5c), all showing positive NFE2L2 associations most notably in LUSC, that based on RNA-seq data appears to be part of the same transcript ( RP11-284F21.7 was preferred for RT-qPCR since it is spliced). BCAN is a proteoglycan linked to invasiveness in glioma62, which lacked expression in A549/H838 but interestingly showed an inverse association with NFE2L2 mutations in LUSC ( P =4.5e-4, Wilcoxon rank sum test). RP11-345L23.1 (also called LINC01564 ) is intergenic but 11 kb upstream of GCLC (83 kb from the closest RefSeq isoform) in the antisense orientation (Fig.…”

Glioma infiltration and extracellular matrix: key players and modulators

“…This molecule is produced by neurons as well as astrocytes, and together with versican isoform V2, aggrecan, tenascin‐R, and link proteins constitute the HA‐based ECM meshwork of the mature brain. Interestingly, brevican is upregulated in gliomas, and its expression correlates with glioma invasiveness (Dwyer, Bi, Viapiano, & Matthews, ). In high‐grade gliomas, mostly over‐sialylated brevican isoforms are present, which are absent in low‐grade tumors (Viapiano et al, ).…”

Deep Sequencing of Complex Proteoglycans: A Novel Strategy for High Coverage and Site-specific Identification of Glycosaminoglycan-linked Peptides

“…Brevican is an important component of PNNs expressed in developmentally regulated manner (63). Secreted by neurons and glial cells and incorporated into the brain extracellular matrices, its expression is up-regulated in response to injury (64) in brain tumor microenvironments and has been associated with tumor aggressiveness (65,66). Brevican contains the N-terminal G1 and C-terminal G3 globular domains characteristic of the hyalectans.…”