2. Academic Validation
  3. Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression

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

  • Nat Commun. 2024 Mar 5;15(1):1987. doi: 10.1038/s41467-024-46193-z.
Fatima Khan 1,  Yiyun Lin 2 3,  Heba Ali 1,  Lizhi Pang 1,  Madeline Dunterman 1,  Wen-Hao Hsu 3 4,  Katie Frenis 5 6,  R Grant Rowe 5 6 7,  Derek A Wainwright 1,  Kathleen McCortney 1,  Leah K Billingham 1,  Jason Miska 1,  Craig Horbinski 1 8,  Maciej S Lesniak 1,  Peiwen Chen 9
Affiliations

Affiliations

  • 1 Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
  • 2 Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • 5 Department of Hematology, Boston Children's Hospital, Boston, MA, 02115, USA.
  • 6 Harvard Medical School, Boston, MA, 02115, USA.
  • 7 Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02115, USA.
  • 8 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 9 Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. peiwen.chen@northwestern.edu.
PMID: 38443336 DOI: 10.1038/s41467-024-46193-z
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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