Abstract
Glioblastoma (GBM) is a highly vascularized, heterogeneous tumor, yet antiangiogenic therapies have yielded limited survival benefits. The lack of validated predictive biomarkers for treatment response stratification remains a major challenge. Aminoacyl tRNA synthetase complex-interacting multicomplex proteins (AIMP) 1/2/3 have been implicated in central nervous system diseases, but their roles in gliomas remain unexplored. We investigated their association with angiogenesis and their significance as predictive biomarkers for antiangiogenic treatment response. In this multi-cohort retrospective study, we analyzed glioma samples from The Cancer Genome Atlas, Chinese Glioma Genome Atlas, REMBRANDT, Gravendeel, BELOB, and REGOMA trials, and four single-cell transcriptomic datasets. Multiomic analyses incorporated transcriptomic, epigenetic, and proteomic data. Kaplan-Meier and Cox proportional hazards models were used to assess the potential prognostic value of AIMPs in heterogeneous and homogeneous treatment groups. Using single-cell transcriptomics, we explored spatial and cell type-specific AIMP2 expression in GBM. AIMP1/2/3 expressions correlated significantly with angiogenesis across The Cancer Genome Atlas cancers. In gliomas, AIMPs were upregulated in tumor versus normal tissues, higher- versus lower-grade gliomas, and recurrent versus primary tumors (P < 0.05). Upon retrospective analysis of two clinical trials assessing different antiangiogenic drugs, we found that high-AIMP2 subgroups had improved response to therapies in GBM [REGOMA: HR, 4.75 (1.96-11.5), P < 0.001; BELOB: HR, 2.3 (1.17-4.49), P = 0.015]. AIMP2-cg04317940methylation emerged as a clinically applicable stratification marker. Single-cell analysis revealed homogeneous AIMP2 expression in tumor tissues, particularly in astrocyte-like cells, suggesting a mechanistic link to tumor angiogenesis. These findings provide novel insights into the role of AIMPs in angiogenesis, offering improved patient stratification and therapeutic outcomes in recurrent GBM. SIGNIFICANCE: This study identifies AIMP2 as a novel biomarker predictive of antiangiogenic treatment response in recurrent GBM. Through multiomic and single-cell analyses, AIMP2 is shown to be upregulated in aggressive gliomas and linked to angiogenesis. Its expression and methylation status offer a clinically applicable stratification tool, enabling more personalized therapeutic approaches and improved outcomes in patients receiving antiangiogenic therapies.