Ectosomal PKM2 Promotes HCC by Inducing Macrophage Differentiation and Remodeling the Tumor Microenvironment

Posted: 2020-06-10   Visits: 10

Abstract: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.