NOTCH1 and ADORA3 define a novel transdifferentiation-related prognostic index for prognostic stratification in glioblastoma by integrating clinical factors.
Abstract
BACKGROUND/
Objectives
Glioblastoma (GBM) exhibits aggressive progression and poor prognosis, partly driven by glioma stem cell-endothelial transdifferentiation (GSC-ET), an alternative vascularization mechanism associated with therapeutic resistance. However, robust prognostic models based on transdifferentiation-related genes remain lacking. This study aimed to identify key GSC-ET-associated genes and develop a personalized prognostic framework integrating molecular and clinical factors.
Methods
Transcriptomic and clinical data from patients with primary IDH-wildtype GBM were obtained from CGGA, TCGA, Gravendeel (GSE16011), and Murat (GSE7696) cohorts. Survival analyses and Cox regression were performed to identify prognostic transdifferentiation-related genes. A glioblastoma transdifferentiation (GTN) index was established based on candidate genes and integrated with clinical variables to construct a prognostic risk model. External validation, immune infiltration analysis, and functional assays were conducted.
Results
Among 12 transdifferentiation-related genes, NOTCH1 and ADORA3 were identified as independent adverse prognostic factors in GBM. A GTN index derived from these genes effectively stratified patient survival and was validated across external cohorts. Integration of the GTN index with age and chemotherapy status generated a risk model with favorable predictive performance and clinical utility. Immune analyses revealed distinct associations between NOTCH1/ADORA3 expression and immune cell infiltration. Functional experiments demonstrated that silencing either gene suppressed tube formation, reduced CD31 expression, and impaired LDL uptake in glioma cells.
Conclusions
NOTCH1 and ADORA3 are associated with GBM prognosis, and their silencing reduces transdifferentiation-related endothelial-like phenotypes, supporting their inclusion in an integrated prognostic framework.