Neuron-like lineage differentiation induced by exogenous Neurexin-1 as a potential therapeutic strategy for glioma.

Strategically altering tumor cell fate is a promising treatment for suppressing the malignant phenotype and improving glioma prognosis. This study reveals the favorable impact of the enrichment of neuronal differentiation-related genes on glioma prognosis. A substantial negative correlation was observed between neuronal and mesenchyme-related biological features within gliomas. Neuron-like tumor cells exhibited relatively low treatment resistance and were prevalent in samples with favorable prognostic scores. By reconstructing the glioblastoma multiforme (GBM) hierarchy, we identified astrocyte-like tumor cells with the highest differentiation potential that play a pivotal role in tumor lineage transition. Subsequent analysis of cell interactions revealed that neuron-like tumor cells engage mainly in the tumor cell network through the neurexin (NRXN) pathway, with astrocyte-like tumor cells being the primary receiver of the pathway. Further in vitro and in vivo experiments demonstrated that exogenous neurexin-1 (NRXN1) has the capacity to regulate the fate of tumor cells, counteract the malignant phenotype, and improve the prognosis of GBM. Furthermore, NRXN1 addition resulted in the downregulation of genes in the activating protein 1 complex. In conclusion, our study revealed that the enrichment of neuronal differentiation-related genes improves glioma prognosis and clarified the role of NRXN1 in regulating tumor cell fate toward the neuronal lineage, suppressing malignant phenotypes, and improving GBM prognosis.