Noor Humaira, Zheng Yuanning, Itakura Haruka, Gevaert Olivier
Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University School of Medicine, Stanford, California.
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California.
Cancer Res Commun. 2025 Sep 1;5(9):1651-1663. doi: 10.1158/2767-9764.CRC-25-0170.
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.
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.
胶质母细胞瘤（GBM）是一种血管高度丰富的异质性肿瘤，但抗血管生成疗法带来的生存获益有限。缺乏用于治疗反应分层的经过验证的预测生物标志物仍然是一个重大挑战。氨酰tRNA合成酶复合物相互作用多复合物蛋白（AIMP）1/2/3与中枢神经系统疾病有关，但其在胶质瘤中的作用仍未得到探索。我们研究了它们与血管生成的关联以及作为抗血管生成治疗反应预测生物标志物的意义。在这项多队列回顾性研究中，我们分析了来自癌症基因组图谱（The Cancer Genome Atlas）、中国胶质瘤基因组图谱（Chinese Glioma Genome Atlas）、REMBRANDT、Gravendeel、BELOB和REGOMA试验的胶质瘤样本，以及四个单细胞转录组数据集。多组学分析纳入了转录组、表观遗传和蛋白质组数据。使用Kaplan-Meier和Cox比例风险模型评估AIMPs在异质性和同质性治疗组中的潜在预后价值。通过单细胞转录组学，我们探索了GBM中AIMP2的空间和细胞类型特异性表达。在癌症基因组图谱中的各种癌症中，AIMP1/2/3的表达与血管生成显著相关。在胶质瘤中，与正常组织相比、高级别与低级别胶质瘤相比、复发与原发性肿瘤相比，AIMPs在肿瘤组织中上调（P < 0.05）。在对两项评估不同抗血管生成药物的临床试验进行回顾性分析时，我们发现高AIMP2亚组在GBM中对治疗的反应有所改善[REGOMA：风险比（HR），4.75（1.96 - 11.5），P < 0.001；BELOB：HR，2.3（1.17 - 4.49），P = 0.015]。AIMP2-cg04317940甲基化成为一种临床适用的分层标志物。单细胞分析显示肿瘤组织中AIMP2表达均匀，特别是在星形胶质细胞样细胞中，这表明与肿瘤血管生成存在机制上的联系。这些发现为AIMPs在血管生成中的作用提供了新的见解，有望改善复发性GBM患者的分层和治疗效果。
本研究确定AIMP2是复发性GBM中抗血管生成治疗反应的一种新型生物标志物。通过多组学和单细胞分析，表明AIMP2在侵袭性胶质瘤中上调并与血管生成相关。其表达和甲基化状态提供了一种临床适用的分层工具，能够在接受抗血管生成治疗的患者中实现更个性化的治疗方法并改善治疗效果。
