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

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 and Peiwen Chen ()
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Fatima Khan: Northwestern University
Yiyun Lin: The University of Texas MD Anderson Cancer Center
Heba Ali: Northwestern University
Lizhi Pang: Northwestern University
Madeline Dunterman: Northwestern University
Wen-Hao Hsu: The University of Texas MD Anderson Cancer Center
Katie Frenis: Boston Children’s Hospital
R. Grant Rowe: Boston Children’s Hospital
Derek A. Wainwright: Northwestern University
Kathleen McCortney: Northwestern University
Leah K. Billingham: Northwestern University
Jason Miska: Northwestern University
Craig Horbinski: Northwestern University
Maciej S. Lesniak: Northwestern University
Peiwen Chen: Northwestern University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46193-z

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