C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1.
C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1.
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DOI：
10.1038/s41419-021-04028-5
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发表时间：
2021-07-26
影响因子：
9
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Ou B;Liu Y;Yang X;Xu X;Yan Y;Zhang J
中性粒细胞是实体肿瘤的重要组成部分，在不同类型的肿瘤中发挥不同的功能。然而，中性粒细胞在乳腺癌（BC）进展中的确切作用目前尚不清楚。在这项研究中，通过调查单细胞RNA测序数据，我们确定了一个新的中性粒细胞亚群，C5 aR 1阳性中性粒细胞，与肿瘤进展和BC患者的生存率低相关。此外，发现C5 aR 1阳性中性粒细胞通过上调ENO 1表达来增强BC细胞糖酵解。在机械上，C5 aR 1阳性嗜酸性粒细胞分泌的IL 1 β和TNFα协同激活ERK 1/2信号传导，其在丝氨酸341处磷酸化WTAP，从而稳定WTAP蛋白。WTAP的稳定化进一步促进ENO 1的RNA m6 A甲基化，影响BC细胞的糖酵解活性。重要的是，C5 aR 1阳性中性粒细胞也促进体内乳腺癌的生长，这种作用被WTAP沉默消除。在临床BC样本中，C5 aR 1阳性中性粒细胞增加与IL 1 β、TNFα和ENO 1表达升高相关。与低共表达相比，C5 aR 1阳性中性粒细胞基因签名和ENO 1的高共表达预测BC患者的预后更差。总的来说，我们的研究揭示了一种新的C5 aR 1阳性中性粒细胞亚群，其通过增加ERK 1/2-WTAP依赖的ENO 1 m6 A甲基化来诱导乳腺癌糖酵解。这些发现支持了探索C5 aR 1阳性中性粒细胞作为乳腺癌治疗靶点的潜力。
Neutrophils are significant compositions of solid tumors and exert distinct functions in different types of tumors. However, the precise role of neutrophils in the progression of breast cancer (BC) is presently unclear. In this study, by investigating the single-cell RNA sequencing data, we identify a new neutrophil subset, C5aR1-positive neutrophils, that correlates with tumor progression and poor survival for BC patients. Furthermore, it is discovered that C5aR1-positive neutrophils enhance BC cell glycolysis via upregulating ENO1 expression. Mechanically, C5aR1-positive neutrophil-secreted IL1β and TNFα cooperatively activate ERK1/2 signaling, which phosphorylates WTAP at serine341 and thereby stabilizes WTAP protein. The stabilization of WTAP further promotes RNA m6A methylation of ENO1, impacting the glycolytic activity of BC cells. Importantly, C5aR1-positive neutrophils also promote breast cancer growth in vivo, and this effect is abolished by WTAP silencing. In clinical BC samples, increased C5aR1-positive neutrophils correlate with elevated IL1β, TNFα, and ENO1 expression. A high co-expression of C5aR1-positive neutrophil gene signature and ENO1 predicts worse prognosis of BC patients compared with a low co-expression. Collectively, our study reveals a novel subset of C5aR1-positive neutrophils that induces breast cancer glycolysis via increasing ERK1/2-WTAP-dependent m6A methylation of ENO1. These findings support the potential for exploration of C5aR1-positive neutrophils as a therapeutic target in breast cancer.
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影响因子：
9
作者：
Sorci M;Ianniello Z;Cruciani S;Larivera S;Ginistrelli LC;Capuano E;Marchioni M;Fazi F;Fatica A
通讯作者：
Fatica A
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
50.3
作者：
Granot Z;Henke E;Comen EA;King TA;Norton L;Benezra R
通讯作者：
Benezra R
影响因子：
64.8
作者：
Finisguerra V;Di Conza G;Di Matteo M;Serneels J;Costa S;Thompson AA;Wauters E;Walmsley S;Prenen H;Granot Z;Casazza A;Mazzone M
通讯作者：
Mazzone M
影响因子：
50.3
作者：
Singhal S;Bhojnagarwala PS;O'Brien S;Moon EK;Garfall AL;Rao AS;Quatromoni JG;Stephen TL;Litzky L;Deshpande C;Feldman MD;Hancock WW;Conejo-Garcia JR;Albelda SM;Eruslanov EB
通讯作者：
Eruslanov EB