Clathrin light chain A‐enriched small extracellular vesicles remodel microvascular niche to induce hepatocellular carcinoma metastasis

Abstract

Abstract Small extracellular vesicles (sEVs) play a key role in exchanging cargoes between cells in tumour microenvironment. This study aimed to elucidate the functions and mechanisms of hepatocellular carcinoma (HCC) derived sEV‐clathrin light chain A (CLTA) in remodelling microvascular niche. CLTA level in the circulating sEVs of HCC patients was analysed by enzyme‐linked immunosorbent assay (ELISA). The functions of sEV‐CLTA in affecting HCC cancerous properties were examined by multiple functional assays. Mass spectrometry was used to identify downstream effectors of sEV‐CLTA in human umbilical vein endothelial cells (HUVECs). Tube formation, sprouting, trans‐endothelial invasion and vascular leakiness assays were performed to determine the functions of sEV‐CLTA and its effector, basigin (BSG) in HUVECs. BSG inhibitor, SP‐8356, was tested in a mouse model of patient‐derived xenografts (PDXs). Circulating sEVs of HCC patients had markedly enhanced CLTA levels than control individuals and were reduced in patients after surgery. HCC derived sEV‐CLTA enhanced HCC cancerous properties, disrupted endothelial integrity and induced angiogenesis. Mechanistically, CLTA remodels microvascular niche by stabilizing and upregulating BSG. Last, SP‐8356 alone or in combination with sorafenib attenuated PDXs growth. The study reveals the role of HCC derived sEV‐CLTA in microvascular niche formation. Inhibition of CLTA and its mediated pathway may illuminate a new therapeutic strategy for HCC patients.

Keywords

• clathrin light chain A
• hepatocellular carcinoma
• intercellular communication
• premetastatic niche
• small extracellular vesicles
• vascular permeability