Patient-derived extracellular vesicles drive cancer stemness and tumorigenesis in hepatocellular carcinoma via polymeric immunoglobulin receptor

ABSTRACT: Background & Aims: Extracellular vesicles (EVs) play a pivotal role in connecting tumor cells and their local and distant microenvironment. Here, we aimed to understand the role and molecular basis of patient-derived EVs in modulating cancer stemness and tumorigenesis in the context of hepatocellular carcinoma (HCC). Methods: EVs were isolated, quantified and characterized from patients’ sera. EVs were tested vigorously, both in vitro and in vivo, by various functional assays. Proteomic analysis was performed to identify the functional components of EVs. The expression level of polymeric immunoglobulin receptor (pIgR) in circulating EVs, tumor and non-tumorous tissues of HCC patients was determined by ELISA, immunoblotting, immunohistochemistry and quantitative PCR. The functional role and underlying mechanism of EVs with an enhanced pIgR expression was elucidated. Blockage of EV-pIgR with neutralizing antibody was performed in nude mice implanted with patient-derived tumor xenograft (PDTX). Results: Circulating EVs of late-stage HCC (L-HCC) patient had significantly elevated pIgR expression when compared to the EVs released by control individuals. The augmenting effect of L-HCC patient in cancer stemness and tumorigenesis was hindered by anti-pIgR antibody. EVs enriched with pIgR consistently promoted cancer stemness and cancerous phenotypes in the recipient cells. Mechanistically, EV-pIgR-induced cancer aggressiveness was abrogated by Akt and β-catenin inhibitors, ascertaining the role of EV-pIgR through the activation of PDK1/Akt/GSK3β/β-catenin signaling axis. Furthermore, anti-pIgR neutralizing antibody attenuated the tumor growth in mice implanted with PDTX. Conclusion: The study illustrates an unrevealed role of EV-pIgR in regulating cancer stemness and aggressiveness, in which EV-pIgR activates PDK1/Akt/GSK3β/β-catenin signaling cascades. The blockage of intercellular communications mediated by EV-pIgR in the tumor microenvironment may provide a new therapeutic strategy for cancer patients.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Liver

DISEASE(S): Liver Cancer

SUBMITTER: Sze Keong Tey  

LAB HEAD: Dr Judy WP Yam

PROVIDER: PXD025522 | Pride | 2023-10-24

REPOSITORIES: Pride