Ectosomal PKM2 Promotes HCC by Inducing Macrophage Differentiation and Remodeling the Tumor Microenvironment
Ectosomal PKM2 Promotes HCC by Inducing Macrophage Differentiation and Remodeling the Tumor Microenvironment
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外体 PKM2 通过诱导巨噬细胞分化和重塑肿瘤微环境促进 HCC
DOI：
10.1016/j.molcel.2020.05.004
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发表时间：
2020-06-18
期刊：
影响因子：
16
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
--
作者：
Hou, Pei-pei;Luo, Li-juan;Wu, Qiao
肿瘤源性细胞外囊泡是肿瘤发生过程中细胞间通讯的重要介质。在这里，我们证明了肝细胞癌（HCC）衍生的外泌体重塑肿瘤微环境，以外泌体PKM 2依赖的方式促进HCC进展。HCC衍生的外体PKM 2不仅诱导单核细胞的代谢重编程，而且还诱导细胞核中的STAT 3磷酸化，以上调分化相关转录因子，导致单核细胞向巨噬细胞分化和肿瘤微环境重塑。在HCC细胞中，PKM 2的sumoylation诱导其质膜靶向和随后的外体排泄通过与ARRDC 1的相互作用。巨噬细胞分泌的细胞因子/趋化因子以CCL 1-CCR 8轴依赖的方式加强了HCC中PKM 2-ARRDC 1的关联，进一步促进HCC细胞分泌PKM 2，形成肿瘤发生的前馈调节环。在临床上，在HCC患者的血浆中明确检测到外体PKM 2。这项研究强调了外体PKM 2重塑肿瘤微环境的机制，并揭示了外体PKM 2作为HCC的潜在诊断标志物。
Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.