N-acetylaspartate release by glutaminolytic ovarian cancer cells sustains protumoral macrophages.
N-acetylaspartate release by glutaminolytic ovarian cancer cells sustains protumoral macrophages.
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DOI：
10.15252/embr.202051981
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发表时间：
2021-09-06
期刊：
影响因子：
7.7
通讯作者：
Castegna A
中科院分区：
文献类型：
--
作者：
Menga A;Favia M;Spera I;Vegliante MC;Gissi R;De Grassi A;Laera L;Campanella A;Gerbino A;Carrà G;Canton M;Loizzi V;Pierri CL;Cormio G;Mazzone M;Castegna A
已知谷氨酰胺溶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是难以捉摸的。在这里，我们表明，卵巢癌细胞变得依赖于细胞外谷氨酰胺时，沉默谷氨酰胺合成酶（GS），类似于天然存在的GS-低，氨酰胺分解-高卵巢癌细胞。谷氨酰胺成瘾引起串扰机制，由此癌细胞释放N-乙酰天冬氨酸（NAA），其通过抑制NMDA受体并与IL-10协同作用，强制巨噬细胞中的GS表达。反过来，GS高巨噬细胞获得M2样致瘤特征。支持这种体外模型，计算机数据和从卵巢癌患者中分离的腹水分析证明，M2样巨噬细胞表型，IL-10释放和NAA水平与疾病分期呈正相关。我们的研究揭示了谷氨酰胺代谢在调节高度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。这项研究揭示了卵巢癌细胞和肿瘤相关巨噬细胞之间的串扰。谷氨酰胺成瘾的癌细胞释放信号代谢物N-乙酰天冬氨酸（NAA），这反过来又使巨噬细胞向GS-高，M2-样状态极化。
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. This study reveals a crosstalk between ovarian cancer cells and tumor associated macrophages. Glutamine addicted cancer cells release the signaling metabolite N‐acetylaspartate (NAA), which in turn polarizes macrophages towards a GS‐high, M2‐like state.
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影响因子：
5.8
作者：
Chauhan A;Sun Y;Sukumaran P;Quenum Zangbede FO;Jondle CN;Sharma A;Evans DL;Chauhan P;Szlabick RE;Aaland MO;Birnbaumer L;Sharma J;Singh BB;Mishra BB
通讯作者：
Mishra BB
影响因子：
4.4
作者：
Adhikary T;Wortmann A;Finkernagel F;Lieber S;Nist A;Stiewe T;Wagner U;Müller-Brüsselbach S;Reinartz S;Müller R
通讯作者：
Müller R
影响因子：
4.3
作者：
Drews L;Zimmermann M;Westhoff P;Brilhaus D;Poss RE;Bergmann L;Wiek C;Brenneisen P;Piekorz RP;Mettler-Altmann T;Weber APM;Reichert AS
通讯作者：
Reichert AS
影响因子：
3.5
作者：
Castegna A;Menga A
通讯作者：
Menga A
影响因子：
9.9
作者：
Gaglio, Daniela;Metallo, Christian M.;Chiaradonna, Ferdinando
通讯作者：
Chiaradonna, Ferdinando