Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression

• Published in: Nature communications Vol. 15; no. 1; pp. 1987 - 20
• Main Authors: Khan, Fatima, Lin, Yiyun, Ali, Heba, Pang, Lizhi, Dunterman, Madeline, Hsu, Wen-Hao, Frenis, Katie, Grant Rowe, R., Wainwright, Derek A., McCortney, Kathleen, Billingham, Leah K., Miska, Jason, Horbinski, Craig, Lesniak, Maciej S., Chen, Peiwen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.03.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/2; 13/21; 13/31; 13/51; 14/19; 14/34; 38; 38/15; 38/77; 38/91; 45/90; 49/98; 631/250/2504/342; 631/67/2327; 631/67/327; 64/110; 64/60; 82/29; 96/95; Animal models; Animals; Biomarkers; Cell survival; Chemokines; Dehydrogenase; Dehydrogenases; Extracellular signal-regulated kinase; Glioblastoma; Glioblastoma - genetics; Glioblastoma cells; Glycolysis; Humanities and Social Sciences; Humans; Infiltration; Kinases; L-Lactate dehydrogenase; L-Lactate Dehydrogenase - genetics; Lactate dehydrogenase; Lactate Dehydrogenase 5; Lactic Acid; Leukocyte migration; Macrophages; Metabolism; Metastases; Mice; Monocyte chemoattractant protein 1; multidisciplinary; Science; Science (multidisciplinary); Stat3 protein; Stiripentol; Symbiosis; Therapeutic targets; Transcription factors; Tumor Microenvironment; Tumors; Yes-associated protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-46193-z

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. Macrophage infiltration and metabolic rewiring are associated with glioblastoma. Here the authors show that the glycolytic enzyme lactate dehydrogenase-A mediates macrophage-cancer cell crosstalk to promote glioblastoma progression.