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[Preprint]. 2025 Mar 14:2025.03.13.643116.
doi: 10.1101/2025.03.13.643116.

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

Humaira Noor  1 , Yuanning Zheng  1 , Haruka Itakura  2 , Olivier Gevaert  1   3
Affiliations

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

Humaira Noor et al. bioRxiv. .

Update in

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: These findings provide novel insights into the role of AIMPs in angiogenesis, offering improved patient stratification and therapeutic outcomes in recurrent GBM.

Keywords: AIMP2; Glioblastoma; anti-angiogenesis treatment; bevacizumab response.

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Conflict of interest statement

Conflict of interest statement The authors declare no potential conflicts of interest.

Figures

Figure 1.
Figure 1.. AIMP1/2/3 correlates with angiogenesis pathway gene-sets.
Correlation between AIMP1/2/3 mRNA expression and (A) 141 Panther pathway angiogenesis gene set and (B) 76 KEGG pathway angiogenesis gene set. The color map represents R value. *asterisk represents statistically significant correlation (Pearson’s correlation p<0.05). N.S represents statistically insignificant cases.
Figure 2.
Figure 2.. AIMP1/2/3 are differentially expressed in glioma tissues.
AIMP1/2/3 (A) mRNA and (B & C) protein expression in TCGA-GBM, TCGA-LGG and normal brain (GTex) tissues. Data for (B) and (C) were collected from the Human Protein Atlas. Student’s t-test * p<0.05.
Figure 3.
Figure 3.. AIMPs are associated with tumor aggressiveness, recurrence and prognosis.
AIMPs mRNA expression levels in (Ai) low (II; n=103) and high-grade (III & IV; n=218) gliomas, and (Aii) primary (n=229) and recurrent gliomas (n=62) in CGGA dataset. Student’s t-test p-value<0.05 considered statistically significant. (B) Kaplan-Meier Survival Curves depicting prognostic effects of AIMP1/2/3 mRNA expressions in CGGA, TCGA, REMBRANDT and Gravendeel cohorts of GBM. Red=high-expression green=low-expression based on median-cutoff; log-rank p-value<0.05 is considered significant.
Figure 4.
Figure 4.. High AIMP mRNA expression subgroups are more responsive to anti-angiogenic therapies.
Kaplan-Meier survival analysis on retrospective clinical trials of recurrent GBM (REGOMA and BELOB trials). High expression sub-groups are stratified by median mRNA expressions of AIMP1/2/3. Log-rank p-value<0.05 is considered significant.
Figure 5.
Figure 5.. Bevacizumab treatment response is associated with specific AIMP CpG site methylation status in gliomas.
(A) Significant association between two CpG sites and astrocytoma (n=22) pathological response to bevacizumab treatment. Student’s t-test p-value<0.05 considered significant (B) Forest plots depicting Cox proportional hazards model univariate (i) and multivariate (ii) analysis for the effects of AIMP1/2/3 CpG methylation status
Figure 6.
Figure 6.. Spatial and cell-type-specific expression of AIMP2 in glioblastoma (GBM) tumors.
(A) Spatial distribution of AIMP2 expression across tumor tissues in two representative GBM slides (i: Slide 334_T, ii: Slide 268_T) analyzed using a spatial transcriptomic dataset. The heatmaps display homogeneous expression of AIMP2 with varying intensity from low (purple) to high (yellow), indicating the absence of localized expression hotspots. (B) Violin plots representing AIMP2 expression across GBM cellular subtypes. (i) AIMP2 expression in key GBM subtypes, including MES-like, AC-like, OPC-like, and NPC-like cells from a concatenated single-cell RNA-seq cohort (Kruskal-Wallis p = 2.32e-02). (ii) AIMP2 expression across malignant GBM subtypes from a spatial transcriptomic dataset. (Kruskal-Wallis p = 1.32e-03).
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