GPR56 signaling pathway network and its dynamics in the mesenchymal transition of glioblastoma

Abstract

G protein-coupled receptor 56 (GPR56/ADGRG1) is a multifunctional adhesion GPCR involved in diverse biological processes ranging from development to cancer. In our earlier study, we reported that GPR56 is expressed heterogeneously in glioblastoma (GBM) and is involved in the mesenchymal transition, making it a promising therapeutic target (Ganesh et al., 2022). Despite its important role in cancer, its mechanism of action or signaling is not completely understood. Thus, based on transcriptomic, proteomic, and phosphoproteomic differential expression data of GPR56 knockdown U373-GBM cells included in our above study along with detailed literature mining of the molecular events plausibly associated with GPR56 activity, we have constructed a signaling pathway map of GPR56 as may be applicable in mesenchymal transition in GBM. The map incorporates more than 100 molecular entities including kinases, receptors, ion channels, and others associated with Wnt, integrin, calcium signaling, growth factors, and inflammation signaling pathways. We also considered intracellular and extracellular factors that may influence the activity of the pathway entities. Here we present a curated signaling map of GPR56 in the context of GBM and discuss the relevance and plausible cross-connectivity across different axes attributable to GPR56 function.

Immune cell infiltration and inflammatory landscape in primary brain tumours

“…In line with these observations, pathways commonly activated in various human PBTs and promoting invasiveness and the expression of pro-inflammatory molecules [20] involved in the regulation of TME infiltrates are those mediated by 5-Lipoxygenases (5-LOX) [21,22], COX-2 and cytokines [23,24] with oncogenic properties [18]. Interestingly, a multifunctional enzyme, the transglutaminase 2 (TG2) might have a role in the inflammatory processes, through NF-κB upregulation and, mesenchymal transition promotion in GBM [25,26]. In this context, previous research showed an increased CD4 + and CD8 + T cell and natural killer (NK) cell infiltration in the TME of lower grade gliomas (LGGs), and conversely a sparse infiltration in immunosuppressed high-grade gliomas (HGGs) [27][28][29].…”