N ‐acetylaspartate release by glutaminolytic ovarian cancer cells sustains protumoral macrophages

Abstract

Glutaminolysis is known to correlate with ovarian cancer aggressiveness and invasion. However, how this affects the tumor microenvironment is elusive. Here, we show that ovarian cancer cells become addicted to extracellular glutamine when silenced for glutamine synthetase (GS), similar to naturally occurring GS‐low, glutaminolysis‐high ovarian cancer cells. Glutamine addiction elicits a crosstalk mechanism whereby cancer cells release N‐acetylaspartate (NAA) which, through the inhibition of the NMDA receptor, and synergistically with IL‐10, enforces GS expression in macrophages. In turn, GS‐high macrophages acquire M2‐like, tumorigenic features. Supporting this in␣vitro model, in silico data and the analysis of ascitic fluid isolated from ovarian cancer patients prove that an M2‐like macrophage phenotype, IL‐10 release, and NAA levels positively correlate with disease stage. Our study uncovers the unprecedented role of glutamine metabolism in modulating macrophage polarization in highly invasive ovarian cancer and highlights the anti‐inflammatory, protumoral function of NAA.

Metabolic Features of Brain Function with Relevance to Clinical Features of Alzheimer and Parkinson Diseases

“…Previous findings indicate that cholinergic treatment could induce elevated NAA levels in AD [ 287 , 288 ], and that this effect could be reversed by other therapeutic strategies [ 289 , 290 ], suggesting a possible influence of dietary regimens or pharmacological treatments on NAA levels measured in AD subjects. The recent finding that NAA could mitigate the inflammatory response of macrophages through NMDAR interaction [ 291 ] clearly opens interesting clues with respect to the role of this metabolite in the neurodegenerative processes underlying the pathologies of AD and PD.…”

Metabolic reprogramming of the tumor immune microenvironment in ovarian cancer: A novel orientation for immunotherapy

“…Its metabolism is significantly associated with the aggressiveness of OC, where glutamine synthetase (GS) is silenced in ovarian cancer cells in favor of extracellular glutamine addiction (96, 97). In highly invasive ovarian cancer, macrophages were found to be driven toward the M2-like subtype by glutamine metabolism (98). Nacetylaspartate (NAA) is secreted by ovarian cancer cells as an antagonist to suppress NMDA receptors on macrophages, causing macrophages to assume an M2-like phenotype with increased GS expression (98).…”

Hormone-Glutamine Metabolism: A Critical Regulatory Axis in Endocrine-Related Cancers

“…Gln metabolism can act on immature myeloid cells, CD11b+Gr1+ myeloid cells, macrophages, and T lymphocytes to realize antitumor immune response [ 128 , 129 , 130 , 131 , 132 ].…”

“…STAT3 has been shown to function in cell differentiation, antiapoptotic response, cancer metastasis, and regulating cancer hallmarks, such that it potentiates drug resistance and correlates with highly invasive OVCA cells [ 147 , 149 , 150 , 151 , 152 , 157 , 158 ]. Recently, Menga’s team uncovered the unprecedented role of glutaminolysis in regulating macrophage polarization in highly invasive OVCA and they clarified that this effect links to N-acetylaspartate (NAA) synthesis as its anti-inflammatory and protumoral properties [ 131 ]. Furthermore, glutamine metabolism has also been proven to modulate the metabolism and function of immunosuppressive CD11b+Gr1+ myeloid cells in ovarian cancer, finally influencing the immune environment of tumors and the antitumor immune response [ 132 ].…”