Nidogen 1-enriched extracellular vesicles facilitate extrahepatic metastasis of liver cancer by activating pulmonary lung fibroblasts to secrete tumor necrosis factor receptor 1

ABSTRACT: In hepatocellular carcinoma (HCC) patients with extrahepatic metastasis, the lung is the most frequent site of metastasis. However, how the lung microenvironment favors disseminated cells remains unclear. Here, it is found that nidogen 1 (NID1) in HCC cell-derived EVs promoted pre-metastatic niche formation in the lung by enhancing angiogenesis and pulmonary endothelial permeability to facilitate colonization of cells and extrahepatic metastasis. Anti-NID1 antibody was able to block the lung colonization of tumor cells induced by HCC patient-derived EVs. EV-NID1 also activated fibroblasts, which secreted tumor necrosis factor receptor 1 (TNFR1), facilitated lung colonization of tumor cells and augmented HCC cell motility. In the clinical perspective, analysis of serum EV-NID1 and TNFR1 in HCC patients revealed their positive correlation and association with tumor stages suggesting the potential of these molecules as noninvasive biomarkers for the early detection of HCC. Administration of anti-TNFR1 antibody effectively diminished lung metastasis in mice. In conclusion, these results demonstrated the interplay of HCC EVs and activated fibroblasts in pre-metastatic niche formation and how blockage of their functions inhibits distant metastasis to the lungs. This study offers promise for the new direction of HCC treatment by targeting oncogenic EV components and their mediated pathways.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Yi Man Eva Fung  

LAB HEAD: Judy Wai Ping Yam

PROVIDER: PXD019566 | Pride | 2020-11-17

REPOSITORIES: Pride