乳酸脱氢酶A
肿瘤微环境
癌症研究
三氯化碳
细胞生物学
车站3
STAT蛋白
下调和上调
生物
趋化因子
信号转导
糖酵解
炎症
四氯化碳
基因
生物化学
免疫学
新陈代谢
肿瘤细胞
作者
Fatima Khan,Yiyun Lin,Heba Ali,Lizhi Pang,Madeline Dunterman,Wen-Hao Hsu,Katie Frenis,R. Grant Rowe,Derek A. Wainwright,Kathleen McCortney,Leah K. Billingham,Jason Miska,Craig Horbinski,Maciej S. Lesniak,Peiwen Chen
标识
DOI:10.1038/s41467-024-46193-z
摘要
Abstract Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.
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