Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and high recurrence rates. The complex immune microenvironment of GBM is highly infiltrated by tumor-associated microglia and macrophages (TAM). TAMs are known to be heterogeneous in their functional and metabolic states and can transmit either protumoral or antitumoral signals to glioma cells. Here, we performed bulk RNA sequencing and single-cell RNA sequencing on samples from patients with GBM, which revealed increased ATP synthase expression and oxidative phosphorylation activity in TAMs located in the tumor core relative to the tumor periphery. Both in vitro and in vivo models displayed similar trends of augmented TAM mitochondrial activity, along with elevated mitochondrial fission, glucose uptake, mitochondrial membrane potential, and extracellular ATP (eATP) production by TAMs in the presence of GBM cells. Tumor-secreted factors, including GM-CSF, induced the increase in TAM eATP production. Elevated eATP in the GBM microenvironment promoted glioma growth and invasion by activating the P2X purinoceptor 7 (P2X7R) on glioma cells. Inhibition of the eATP–P2X7R axis attenuated tumor cell viability in vitro and reduced tumor size and prolonged survival in glioma-bearing mouse models. Overall, this study revealed elevated TAM-derived eATP in GBM and provided the basis for targeting the eATP–P2X7R signaling axis as a therapeutic strategy in GBM. Significance: Glioblastoma-mediated metabolic reprogramming in tumor-associated microglia increases ATP secretion that supports cancer cell proliferation and invasion by activating P2X7R, which can be inhibited to attenuate tumor growth.

中文翻译：

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肿瘤相关小胶质细胞分泌细胞外 ATP 以支持胶质母细胞瘤的进展


胶质母细胞瘤 （GBM） 是一种高度侵袭性的脑肿瘤，预后不良，复发率高。GBM 的复杂免疫微环境被肿瘤相关的小胶质细胞和巨噬细胞 （TAM） 高度浸润。已知 TAM 的功能和代谢状态具有异质性，可以将促瘤或抗瘤信号传递到神经胶质瘤细胞。在这里，我们对 GBM 患者的样本进行了批量 RNA 测序和单细胞 RNA 测序，结果显示相对于肿瘤外围位于肿瘤核心的 TAM 中 ATP 合酶表达和氧化磷酸化活性增加。体外和体内模型均显示出 TAM 线粒体活性增强的相似趋势，以及在 GBM 细胞存在下 TAM 产生的线粒体裂变、葡萄糖摄取、线粒体膜电位和细胞外 ATP （eATP） 升高。包括 GM-CSF 在内的肿瘤分泌因子诱导了 TAM eATP 生成的增加。GBM 微环境中 eATP 升高通过激活神经胶质瘤细胞上的 P2X 嘌呤受体 7 （P2X7R） 促进神经胶质瘤的生长和侵袭。在荷脑胶质瘤小鼠模型中，抑制 eATP-P2X7R 轴可减弱体外肿瘤细胞活力，并减小肿瘤大小并延长生存期。总体而言，本研究揭示了 GBM 中 TAM 衍生的 eATP 升高，并为靶向 eATP-P2X7R 信号轴作为 GBM 的治疗策略提供了基础。意义： 胶质母细胞瘤介导的肿瘤相关小胶质细胞代谢重编程通过激活 P2X7R 增加 ATP 分泌，从而支持癌细胞增殖和侵袭，P2X7R 可以被抑制以减轻肿瘤生长。