Two distinct receptor-binding domains of human glycyl-tRNA synthetase 1 displayed on extracellular vesicles activate M1 polarization and phagocytic bridging of macrophages to cancer cells

Cancer Lett. 2022 Jul 28:539:215698. doi: 10.1016/j.canlet.2022.215698. Epub 2022 May 9.


Macrophages play important roles in cancer microenvironment. Human cytosolic glycyl-tRNA synthetase (GARS1) was previously shown to be secreted via extracellular vesicles (EVs) from macrophages to trigger cancer cell death. However, the effects of GARS1-containing EVs (GARS1-EVs) on macrophages as well as on cancer cells and the working mechanisms of GARS1 in cancer microenvironment are not yet understood. Here we show that GARS1-EVs induce M1 polarization and facilitate phagocytosis of macrophages. GARS1-EVs triggers M1 polarization of macrophage via the specific interaction of the extracellular cadherin subdomains 1-4 of the cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2) with the N-terminal WHEP domain containing peptide region of GARS1, and activates the RAF-MEK-ERK pathway for M1 type cytokine production and phagocytosis. Besides, GARS1 interacted with cadherin 6 (CDH6) of cancer cells via its C-terminal tRNA-binding domain to induce cancer cell death. In vivo model, GARS1-EVs showed potent suppressive activity against tumor initiation via M1 type macrophages. GARS1 displayed on macrophage-secreted extracellular vesicles suppressed tumor growth in dual mode, namely through pro-apoptotic effect on cancer cells and M1 polarization effect on macrophages. Collectively, these results elucidate the unique tumor suppressive activity and mechanism of GARS1-EVs by activating M1 macrophage via CELSR2 as well as by direct killing of cancer cells via CDH6.

Keywords: Cadherin EGF LAG seven-pass G-type receptor 2; Cancer microenvironment; Extracellular vesicles; Glycyl-tRNA synthetase 1; Macrophage.

MeSH terms

  • Cadherins / metabolism
  • Cell Polarity
  • Extracellular Vesicles* / enzymology
  • Extracellular Vesicles* / metabolism
  • Glycine-tRNA Ligase* / analysis
  • Glycine-tRNA Ligase* / metabolism
  • Glycine-tRNA Ligase* / pharmacology
  • Humans
  • Macrophages* / enzymology
  • Macrophages* / metabolism
  • Macrophages* / pathology
  • Neoplasms* / enzymology
  • Neoplasms* / metabolism
  • Phagocytosis
  • Tumor Microenvironment


  • Cadherins
  • Glycine-tRNA Ligase