PKM2 Excretion Promotes HCC By Remodeling Tumor Microenvironment

Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumor development.Although substantial attention has focused on the regulatory roles of exosomes in tumor progression,the regulatory functions and mechanisms of ectosomes in tumor microenvironment communication remain elusive.In the current study,PKM2,a rate-limiting glycolytic enzyme,was identified as a pivotal ectosomal mediator by mass spectrometry-based analysis of the proteome of hepatoma cell-derived ectosomes.Once releasing,HCC cell-derived ectosomal PKM2 was taken up by circulating monocytes,which induced expression of differentiation-associated transcription factors in monocytes by activation of glycolytic remodeling to provide acetyl-CoA for the histone acetylation,and by phosphorylation of STAT3 at Y705 to enhance its transcriptional activity,and thereby leads to monocyte-to-macrophage differentiation and tumor microenvironment remodeling.These monocytes/macrophages further potentiate the secretion of cytokines and chemokines to exert regurgitation-feeding activity on tumor cells,which not only promotes HCC cell proliferation directly but also induces more ectosomal excretion of PKM2 from HCC cells.Among these factors,CCL1 exerts a signaling cascade by interaction with its receptor CCR8 expressed on HCC cells to potentiate ARRDC1-mediated PKM2 excretion.The CCL1-CCR8 axis thus mediates a feed-forward loop between HCC cells and macrophaes,which eventually promotes HCC progression.Finally,both in the HCC mouse model and in clinical samples,HCC-derived ectosomal PKM2 was clearly detected and elevated in plasma from HCC mice or patients.In sum,this study not only demonstrates a novel protumoral role of HCC-derived ectosomal PKM2 in mediating intercellular communicaton in liver tumor microenvironment,but also reveals plasma ectosomal PKM2 as a promising clinical diagnostic marker and therapeutic target for HCC.