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. (28th July 2022)

• Record Type: Journal Article
• Authors: Park, Min Chul; Goughnour, Peter C.; Jun, Sangmi; Cho, Seongmin; Song, Eunjoo; Kim, Sang Bum; Kim, Hyeong Yun; Hyun, Jae Kyung; Kim, Pilhan; Jung, Hyun Suk; Kim, Sunghoon
• Is Part Of: Cancer letters. Volume 539(2022)
• Publication Date: 2022-07-28
• Subjects: Glycyl-tRNA synthetase 1 -- Extracellular vesicles -- Macrophage -- Cancer microenvironment -- Cadherin EGF LAG seven-pass G-type receptor 2; TLR4 Toll-like receptor 4; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215698
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: Secreted GARS1 induces M1 polarization of macrophages. GARS1 surface displayed vesicles strongly suppress tumor initiation via M1 macrophage polarization. M1 polarization is mediated by the interaction of GARS1 with CELSR2 on macrophages.