Zhao Jianyi, Wu Linshi, Cai Gang, Ou Dan, Liao Keman, Yang Jian, Zhou Li, Huang Renhua, Lin Shukai, Huang Xi, Lv Qi, Chen Juxiang, Cao Lu, Chen Jiayi, Lin Yingying
Shanghai Key Laboratory of Proton-Therapy, Shanghai, China.
Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Neuro Oncol. 2025 Jul 30;27(6):1491-1506. doi: 10.1093/neuonc/noaf045.
Recent studies have highlighted bidirectional signaling between tumors and neurons; however, the interactions between tumors and neurons in response to radio-/chemotherapy remain obscure, which hampers the tumor treatment.
Glioblastoma organoids (GBOs) and primary neuron coculture, targeted metabonomics, RNA pulldown, mass spectrum, co-immunoprecipitation, RNA-sequencing, transcript/protein validations, and multi-electrode arrays were performed to analyze neuron-tumor interaction in response to therapy. In vivo validations were conducted in orthotopic mouse models. Diagnostic and prognostic values were evaluated in serum, tissue microarray as well as The Cancer Genome Atlas (TCGA).
GBOs recruited and induced pro-tumor-survival senescent neurons upon radiation/chemotherapeutic treatment. Targeted metabonomics revealed that significantly increased tumor-derived prostaglandin E2 (PGE2) induced neuronal senescence phenotype. Screening of enzymes involved in PGE2 synthesis identified prostaglandin E synthase 3 (PTGES3) as the key enzyme responsible for PGE2 upregulation. Biochemical studies revealed that irradiation or chemotherapeutic drug-triggered asparagine endopeptidase (AEP) specifically cleaved eukaryotic translation initiation factor 4A1 (eIF4A1) to produce truncated C-terminal eIF4A1 (teIF4A1-C), which dissociated from DEAD-box helicase 6 (DDX6) and recruited eIF4A3 and polyadenylate-binding protein nuclear 1 (PABPN1) to promote the mRNA stability of PTGES3. Elevated PGE2 reciprocally enhanced AEP expression. Inhibiting PGE2 or AEP reduced neuronal senescence and delayed tumor progression. Strikingly, single-cell analysis further showed that expressions of AEP/PTGES3/EIF4A1 in tumor cells were consistent with senescent neuronal cyclin-dependent kinase inhibitor 1A (CDKN1A) in high-neuronal-connectivity glioblastoma. The serum PGE2 concentration was elevated after radiation and higher in resistant glioblastoma patients. High expression of PTGES3 was associated with a poor prognosis.
Our study revealed that the AEP/PGE2 feedback loop modulates tumor-induced neuronal senescence upon radio-/chemotherapy and highlights the therapeutic value to improve tumor therapy.
近期研究突显了肿瘤与神经元之间的双向信号传导；然而，肿瘤与神经元在放疗/化疗反应中的相互作用仍不清楚，这阻碍了肿瘤治疗。
进行胶质母细胞瘤类器官（GBOs）与原代神经元共培养、靶向代谢组学、RNA下拉、质谱分析、免疫共沉淀、RNA测序、转录本/蛋白质验证以及多电极阵列，以分析治疗反应中的神经元-肿瘤相互作用。在原位小鼠模型中进行体内验证。在血清、组织微阵列以及癌症基因组图谱（TCGA）中评估诊断和预后价值。
放疗/化疗处理后，GBOs招募并诱导了促肿瘤存活的衰老神经元。靶向代谢组学显示，肿瘤来源的前列腺素E2（PGE2）显著增加，诱导了神经元衰老表型。对参与PGE2合成的酶进行筛选，确定前列腺素E合酶3（PTGES3）是负责PGE2上调的关键酶。生化研究表明，辐射或化疗药物触发的天冬酰胺内肽酶（AEP）特异性切割真核翻译起始因子4A1（eIF4A1），产生截短的C端eIF4A1（teIF4A1-C），其与DEAD盒解旋酶6（DDX6）解离，并招募eIF4A3和聚腺苷酸结合蛋白核1（PABPN1）以促进PTGES3的mRNA稳定性。升高的PGE2反过来增强AEP表达。抑制PGE2或AEP可减少神经元衰老并延缓肿瘤进展。引人注目的是，单细胞分析进一步表明，肿瘤细胞中AEP/PTGES3/EIF4A1的表达与高神经元连接性胶质母细胞瘤中衰老神经元细胞周期蛋白依赖性激酶抑制剂1A（CDKN1A）的表达一致。放疗后血清PGE2浓度升高，在耐药胶质母细胞瘤患者中更高。PTGES3的高表达与不良预后相关。
我们的研究表明AEP/PGE2反馈回路在放疗/化疗后调节肿瘤诱导的神经元衰老，并突出了改善肿瘤治疗的治疗价值。
