PUBLICATION

Lactate modulates microglia polarization via IGFBP6 expression and remodels tumor microenvironment in glioblastoma

Authors
Longhitano, L., Vicario, N., Forte, S., Giallongo, C., Broggi, G., Caltabiano, R., Barbagallo, G.M.V., Altieri, R., Raciti, G., Di Rosa, M., Caruso, M., Parenti, R., Liso, A., Busi, F., Lolicato, M., Mione, M.C., Li Volti, G., Tibullo, D.
ID
ZDB-PUB-220607-2
Date
2022
Source
Cancer immunology, immunotherapy : CII   72(1): 1-20 (Journal)
Registered Authors
Keywords
Glioblastoma, IGFBP6, Lactate, Microenvironment, Microglia
MeSH Terms
  • Microglia/metabolism
  • Brain Neoplasms*/pathology
  • Insulin-Like Growth Factor Binding Protein 6/metabolism
  • Insulin-Like Growth Factor Binding Protein 6/therapeutic use
  • Glioblastoma*/pathology
  • Cell Line, Tumor
  • Hedgehog Proteins
  • Tumor Microenvironment
  • Humans
  • Lactic Acid/metabolism
  • Lactic Acid/therapeutic use
  • Zebrafish/metabolism
  • Animals
(all 13)
PubMed
35654889 Full text @ Cancer Immunol Immunother
Abstract
Lactic acidosis has been reported in solid tumor microenvironment (TME) including glioblastoma (GBM). In TME, several signaling molecules, growth factors and metabolites have been identified to induce resistance to chemotherapy and to sustain immune escape. In the early phases of the disease, microglia infiltrates TME, contributing to tumorigenesis rather than counteracting its growth. Insulin-like Growth Factor Binding Protein 6 (IGFBP6) is expressed during tumor development, and it is involved in migration, immune-escape and inflammation, thus providing an attractive target for GBM therapy. Here, we aimed at investigating the crosstalk between lactate metabolism and IGFBP6 in TME and GBM progression. Our results show that microglia exposed to lactate or IGFBP6 significantly increased the Monocarboxylate transporter 1 (MCT1) expression together with genes involved in mitochondrial metabolism. We, also, observed an increase in the M2 markers and a reduction of inducible nitric oxide synthase (iNOS) levels, suggesting a role of lactate/IGFBP6 metabolism in immune-escape activation. GBM cells exposed to lactate also showed increased levels of IGFBP6 and vice-versa. Such a phenomenon was coupled with a IGFBP6-mediated sonic hedgehog (SHH) ignaling increase. We, finally, tested our hypothesis in a GBM zebrafish animal model, where we observed an increase in microglia cells and igfbp6 gene expression after lactate exposure. Our results were confirmed by the analysis of human transcriptomes datasets and immunohistochemical assay from human GBM biopsies, suggesting the existence of a lactate/IGFBP6 crosstalk in microglial cells, so that IGFBP6 expression is regulated by lactate production in GBM cells and in turn modulates microglia polarization.
Genes / Markers
Figures
Figure Gallery (8 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
hzm5Et; io006Tgchemical treatment by environment: lactateDay 5
hzm5Et; io006Tgchemical treatment by environment: lactateDay 5
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hzm5EtTransgenic Insertion
    io006TgTransgenic Insertion
      1 - 2 of 2
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      Human Disease / Model
      Human Disease Fish Conditions Evidence
      glioblastomahzm5Et; io006Tgstandard conditionsTAS
      1 - 1 of 1
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      Sequence Targeting Reagents
      No data available
      Fish
      Antibodies
      Orthology
      Engineered Foreign Genes
      Marker Marker Type Name
      EGFPEFGEGFP
      GAL4TA4EFGGAL4TA4
      mCherryEFGmCherry
      1 - 3 of 3
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      Mapping
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      Citation
      Longhitano, L., Vicario, N., Forte, S., Giallongo, C., Broggi, G., Caltabiano, R., Barbagallo, G.M.V., Altieri, R., Raciti, G., Di Rosa, M., Caruso, M., Parenti, R., Liso, A., Busi, F., Lolicato, M., Mione, M.C., Li Volti, G., Tibullo, D. (2022) Lactate modulates microglia polarization via IGFBP6 expression and remodels tumor microenvironment in glioblastoma. Cancer immunology, immunotherapy : CII. 72(1):1-20.