Wu Caren Yu-Ju, Chen Yiyun, Lin Ya-Jui, Wei Kuo-Chen, Chang Kwang-Yu, Feng Li-Ying, Chen Ko-Ting, Li Gordon, Ren Alexander Liang, Nitta Ryan Takeo, Wu Janet Yuling, Cho Kwang Bog, Pant Ayush, Choi John, Mackall Crystal L, Kim Lily H, Wu An-Chih, Chuang Jian-Ying, Huang Chiung-Yin, Jackson Christopher M, Chen Pin-Yuan, Lim Michael
Department of Neurosurgery, Keelung Chang Gung Medical Foundation, Keelung, Taiwan.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California.
Cancer Res. 2024 Dec 2;84(23):4017-4030. doi: 10.1158/0008-5472.CAN-24-0018.
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.
胶质母细胞瘤（GBM）是一种侵袭性很强的脑肿瘤，预后差且复发率高。GBM复杂的免疫微环境中高度浸润着肿瘤相关小胶质细胞和巨噬细胞（TAM）。已知TAM在功能和代谢状态上具有异质性，可向胶质瘤细胞传递促肿瘤或抗肿瘤信号。在此，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，相对于肿瘤周边，位于肿瘤核心的TAM中ATP合酶表达增加，氧化磷酸化活性增强。体外和体内模型均显示出TAM线粒体活性增强的类似趋势，同时在存在GBM细胞的情况下，TAM的线粒体裂变、葡萄糖摄取、线粒体膜电位和细胞外ATP（eATP）生成均升高。包括GM-CSF在内的肿瘤分泌因子诱导了TAM的eATP生成增加。GBM微环境中升高的eATP通过激活胶质瘤细胞上的P2X嘌呤受体7（P2X7R）促进了胶质瘤的生长和侵袭。抑制eATP-P2X7R轴可在体外减弱肿瘤细胞活力，并在荷瘤小鼠模型中减小肿瘤大小、延长生存期。总体而言，本研究揭示了GBM中TAM来源的eATP升高，并为将eATP-P2X7R信号轴作为GBM的治疗策略提供了依据。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增加了ATP分泌，通过激活P2X7R来支持癌细胞增殖和侵袭，抑制该过程可减弱肿瘤生长。
