Prognostic Neurotransmitter Receptors Genes Are Associated with Immune Response, Inflammation and Cancer Hallmarks in Brain Tumors

SIMPLE SUMMARY: Glioblastoma multiforme (GBM) is an aggressive form of glioma characterized by poor survival rates. The main cause of the limited efficacy of the current treatments and tumor recurrence is associated with the infiltration of GBM cells into the surrounding brain tissue. Until recently, peripheral nerves were believed to play a passive role in tumorigenesis; however, over the last decade, pioneering studies have highlighted their involvement in cancer initiation and progression by releasing neurotransmitters (NTs). In this study, we hypothesized that dysregulated genes encoding for neurotransmitter receptors (NTRs) could have a different association with patient survival in GBM and low-grade glioma (LGG). We identified 10 prognostic NTR genes that are progressively downregulated across cancer grades and are negatively correlated with genes associated with immune response, inflammation, and brain cancer hallmarks in LGG but not in GBM. We believe our findings shed new light on the role of neurotransmitters and their interactions with inflammation and immune response in the malignant progression of human gliomas. ABSTRACT: Glioblastoma multiforme (GBM) is one of the most aggressive forms of cancer. Neurotransmitters (NTs) have recently been linked with the uncontrolled proliferation of cancer cells, but the role of NTs in the progression of human gliomas is still largely unexplored. Here, we investigate the genes encoding for neurotransmitter receptors (NTRs) by analyzing public transcriptomic data from GBM and LGG (low-grade glioma) samples. Our results showed that 50 out of the 98 tested NTR genes were dysregulated in brain cancer tissue. Next, we identified and validated NTR-associated prognostic gene signatures for both LGG and GBM. A subset of 10 NTR genes (DRD1, HTR1E, HTR3B, GABRA1, GABRA4, GABRB2, GABRG2, GRIN1, GRM7, and ADRA1B) predicted a positive prognosis in LGG and a negative prognosis in GBM. These genes were progressively downregulated across glioma grades and exhibited a strong negative correlation with genes associated with immune response, inflammasomes, and established cancer hallmarks genes in lower grade gliomas, suggesting a putative role in inhibiting cancer progression. This study might have implications for the development of novel therapeutics and preventive strategies that target regulatory networks associated with the link between the autonomic nervous system, cancer cells, and the tumor microenvironment.