BLOCKADE OF GLUTAMINE SYNTHETASE SKEWS MACROPHAGES TOWARDS AN M1-LIKE PHENOTYPE AND INHIBITS TUMOR METASTASIS

A Castegna, EM Palmieri, R Martín-Pérez, ALESSIO MENGA, B Ghesquière, M. Mazzone

Risultato della ricerca: Contributo alla conferenzaPoster

Abstract

Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events including the release of inflammatory mediators, mTOR activation and autophagy. However, its role in macrophages remains elusive. Here 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 and pyruvate carboxylase, and consequent HIF1α activation. These metabolic changes and HIF1α accumulation in GS-inhibited macrophages promote M1 markers expression, accompanied by the ability to boost T-cell proliferation and migration, and to impair endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor-bearing mice promotes tumor vessel pruning, vascular normalization and accumulation of cytotoxic T-cells, leading to metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive and prometastatic function of M2-like macrophages and highlight the possibility to target this enzyme in the treatment of cancer metastasis.
Lingua originaleInglese
Stato di pubblicazionePubblicato - 2016
EventoISCAM 2016 - Bruxelles
Durata: 1 gen 2016 → …

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???event.eventtypes.event.conference???ISCAM 2016
CittàBruxelles
Periodo1/01/16 → …

Keywords

  • glutamine synthetase
  • macrophage

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