Zeb1-induced metabolic reprogramming of glycolysis is essential for macrophage polarization in breast cancer.
Zeb1-induced metabolic reprogramming of glycolysis is essential for macrophage polarization in breast cancer.
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DOI：
10.1038/s41419-022-04632-z
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发表时间：
2022-03-04
影响因子：
9
通讯作者：
Yang S
中科院分区：
文献类型：
--
作者：
Jiang H;Wei H;Wang H;Wang Z;Li J;Ou Y;Xiao X;Wang W;Chang A;Sun W;Zhao L;Yang S
有氧糖酵解（瓦尔堡效应）已被证明可以通过产生乳酸来促进肿瘤进展，乳酸作为促炎和免疫抑制介质具有重要作用。然而，有氧糖酵解是如何直接调节的很大程度上尚不清楚。在这里，我们发现异位Zeb1直接增加HK2、PFKP和PKM2（糖酵解速率决定酶）的转录表达，从而促进Warburg效应以及体外和体内乳腺癌的增殖、迁移和化疗耐药性。此外，Zeb1 通过 PI3K/Akt/HIF-1α 信号轴发挥其生物效应，诱导糖酵解活性以应对缺氧，这有助于培育免疫抑制肿瘤微环境 (TME)。从机制上讲，异位表达 Zeb1 的乳腺癌细胞在酸性肿瘤环境中产生乳酸，通过刺激 PKA/CREB 信号通路诱导交替激活 (M2) 巨噬细胞表型。临床上，Zeb1的表达与乳腺癌患者的有氧糖酵解失调、M2样肿瘤相关巨噬细胞（TAM）的积累以及不良预后呈正相关。总之，这些发现确定了 Zeb1 依赖性机制是乳腺癌进展的驱动因素，通过刺激肿瘤-巨噬细胞相互作用发挥作用，这可能是治疗晚期人类癌症的可行治疗靶点。
Aerobic glycolysis (the Warburg effect) has been demonstrated to facilitate tumor progression by producing lactate, which has important roles as a proinflammatory and immunosuppressive mediator. However, how aerobic glycolysis is directly regulated is largely unknown. Here, we show that ectopic Zeb1 directly increases the transcriptional expression of HK2, PFKP, and PKM2, which are glycolytic rate-determining enzymes, thus promoting the Warburg effect and breast cancer proliferation, migration, and chemoresistance in vitro and in vivo. In addition, Zeb1 exerts its biological effects to induce glycolytic activity in response to hypoxia via the PI3K/Akt/HIF-1α signaling axis, which contributes to fostering an immunosuppressive tumor microenvironment (TME). Mechanistically, breast cancer cells with ectopic Zeb1 expression produce lactate in the acidic tumor milieu to induce the alternatively activated (M2) macrophage phenotype through stimulation of the PKA/CREB signaling pathway. Clinically, the expression of Zeb1 is positively correlated with dysregulation of aerobic glycolysis, accumulation of M2-like tumor-associated macrophages (TAMs) and a poor prognosis in breast cancer patients. In conclusion, these findings identify a Zeb1-dependent mechanism as a driver of breast cancer progression that acts by stimulating tumor–macrophage interplay, which could be a viable therapeutic target for the treatment of advanced human cancers.
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影响因子：
29
作者：
Cascone T;McKenzie JA;Mbofung RM;Punt S;Wang Z;Xu C;Williams LJ;Wang Z;Bristow CA;Carugo A;Peoples MD;Li L;Karpinets T;Huang L;Malu S;Creasy C;Leahey SE;Chen J;Chen Y;Pelicano H;Bernatchez C;Gopal YNV;Heffernan TP;Hu J;Wang J;Amaria RN;Garraway LA;Huang P;Yang P;Wistuba II;Woodman SE;Roszik J;Davis RE;Davies MA;Heymach JV;Hwu P;Peng W
通讯作者：
Peng W
影响因子：
8
作者：
Chen, Chong;Bai, Lipeng;Luo, Yunping
通讯作者：
Luo, Yunping
影响因子：
16.6
作者：
Jiang H;Zhou C;Zhang Z;Wang Q;Wei H;Shi W;Li J;Wang Z;Ou Y;Wang W;Wang H;Zhang Q;Sun W;Sun P;Yang S
通讯作者：
Yang S
影响因子：
15.9
作者：
Chao, Chi-Hong;Chang, Chao-Ching;Chang, Chun-Ju
通讯作者：
Chang, Chun-Ju
缺氧诱导的ZEB1通过CCL8依赖性肿瘤相关巨噬细胞募集促进宫颈癌进展
影响因子：
9
作者：
Chen, Xiao-Jing;Deng, Yuan-Run;Wang, Wei
通讯作者：
Wang, Wei