Exploring and Targeting Dysregulated GPCRs in Glioblastoma: A Comprehensive Investigation

Abstract

G protein–coupled receptors (GPCRs) represent the largest family of membrane receptors and are key regulators of cellular signaling. While extensively targeted in various diseases, their potential in oncology especially glioblastoma (GBM) remains underutilized. In this study, we conducted a comprehensive genome-wide analysis of GPCRs, their ligands, and associated G-proteins to delineate their genetic and epigenetic dysregulation in GBM. Approximately 20% of the genes examined were found to be differentially expressed, with miRNA-mediated regulation emerging as a predominant mechanism. Among these, GPR84 was identified as a significantly upregulated GPCR. Functional assays demonstrated that GPR84 knockdown or pharmacological inhibition suppressed GBM cell proliferation, induced apoptosis, and reduced tumor burden in orthotopic xenograft models, establishing its therapeutic relevance.

We carried out in depth investigation of another GPCR, Calcitonin Receptor (CALCR), a class B GPCR associated with poor prognosis when mutated or downregulated in GBM. Proteomic profiling via Reverse Phase Protein Array (RPPA) revealed that Calcitonin (CT) treatment activated CALCR signaling and suppressed oncogenic phenotypes through downregulation of the transcriptional co-activators YAP and TAZ. Mechanistically, this effect was mediated by the cAMP–PKA–LATS signaling axis, functioning independently of MST1. Intranasal delivery of CT in orthotopic GBM mouse models significantly attenuated tumor growth and prolonged survival, highlighting its potential for therapeutic repurposing.

Finally, molecular dynamics (MD) simulations of patient-derived CALCR mutants uncovered mutation-specific disruptions in receptor conformation and dynamics, providing a structural rationale for loss of function. Collectively, our findings illuminate the multifaceted roles of deregulated GPCRs in GBM and underscore the translational promise of targeting GPR84 and CALCR as novel therapeutic strategies