Response to anti-angiogenic therapy is affected by AIMP protein family activity in glioblastoma and lower-grade gliomas.

Glioblastoma (GBM) is a highly vascularized, heterogeneous tumor, yet anti-angiogenic 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 (AIMPs) 1/2/3 have been implicated in CNS diseases, but their roles in gliomas remain unexplored. We investigated their association with angiogenesis and their significance as predictive biomarkers for anti-angiogenic treatment response. In this multi-cohort retrospective study we analyzed glioma samples from TCGA, CGGA, Rembrandt, Gravendeel, BELOB and REGOMA trials, and four single-cell transcriptomic datasets. Multi-omic analyses incorporated transcriptomic, epigenetic, and proteomic data. Kaplan-Meier and Cox proportional hazards models were used to assess the 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 TCGA cancers. In gliomas, AIMPs were upregulated in tumor vs. normal tissues, higher- vs. lower-grade gliomas, and recurrent vs. primary tumors (p<0.05). Upon retrospective analysis of two clinical trials assessing different anti-angiogenic 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-cg04317940 methylation emerged as a clinically applicable stratification marker. Single-cell analysis revealed homogeneous AIMP2 expression in tumor tissues, particularly in AC-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.