TY - JOUR
T1 - Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis
AU - Palmieri, Erika M.
AU - Menga, Alessio
AU - Martín-Pérez, Rosa
AU - Quinto, Annamaria
AU - Riera-Domingo, Carla
AU - de Tullio, Giacoma
AU - Hooper, Douglas C.
AU - Lamers, Wouter H.
AU - Ghesquière, Bart
AU - McVicar, Daniel W.
AU - Guarini, Attilio
AU - Mazzone, Massimiliano
AU - Castegna, Alessandra
PY - 2017
Y1 - 2017
N2 - Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1 alpha activation. As a result of these metabolic changes and HIF1 alpha accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumorbearing mice promotes tumor vessel pruning, vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages and highlight the possibility of targeting this enzyme in the treatment of cancer metastasis
AB - Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1 alpha activation. As a result of these metabolic changes and HIF1 alpha accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumorbearing mice promotes tumor vessel pruning, vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages and highlight the possibility of targeting this enzyme in the treatment of cancer metastasis
U2 - https://doi.org/10.1016/j.celrep.2017.07.054
DO - https://doi.org/10.1016/j.celrep.2017.07.054
M3 - Article
C2 - 28813676
SN - 2211-1247
VL - 20
SP - 1654
EP - 1666
JO - Cell reports
JF - Cell reports
IS - 7
ER -