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.

中文翻译：

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谷氨酰胺分解卵巢癌细胞释放 N-乙酰天冬氨酸维持促肿瘤巨噬细胞

已知谷氨酰胺分解与卵巢癌的侵袭性和侵袭性相关。然而，这如何影响肿瘤微环境尚不清楚。在这里，我们发现，当谷氨酰胺合成酶（GS）沉默时，卵巢癌细胞会对细胞外谷氨酰胺上瘾，类似于天然存在的 GS 低、谷氨酰胺分解高的卵巢癌细胞。谷氨酰胺成瘾会引发一种串扰机制，癌细胞释放N-乙酰天冬氨酸 (NAA)，通过抑制 NMDA 受体，并与 IL-10 协同作用，增强巨噬细胞中 GS 的表达。反过来，GS 高巨噬细胞获得 M2 样的致瘤特征。支持这一体外模型的计算机数据和对卵巢癌患者腹水分离的分析证明，M2 样巨噬细胞表型、IL-10 释放和 NAA 水平与疾病阶段呈正相关。我们的研究揭示了谷氨酰胺代谢在调节高侵袭性卵巢癌巨噬细胞极化中前所未有的作用，并强调了 NAA 的抗炎、促肿瘤功能。