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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

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			Action	DRS
	Judy_27May2020_1_MIHA_1.raw	Raw
	Judy_27May2020_1_MIHA_2.raw	Raw
	Judy_27May2020_1_MIHA_3.raw	Raw
	Judy_27May2020_2_97L_1.raw	Raw
	Judy_27May2020_2_97L_2.raw	Raw

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Nidogen 1-Enriched Extracellular Vesicles Facilitate Extrahepatic Metastasis of Liver Cancer by Activating Pulmonary Fibroblasts to Secrete Tumor Necrosis Factor Receptor 1.

Mao Xiaowen X Tey Sze Keong SK Yeung Cherlie Lot Sum CLS Kwong Ernest Man Lok EML Fung Yi Man Eva YME Chung Clive Yik Sham CYS Mak Lung-Yi LY Wong Danny Ka Ho DKH Yuen Man-Fung MF Ho James Chung Man JCM Pang Herbert H Wong Maria Pik MP Leung Carmen Oi-Ning CO Lee Terence Kin Wah TKW Ma Victor V Cho William Chi-Shing WC Cao Peihua P Xu Xiaoping X Gao Yi Y Gao Yi Y Yam Judy Wai Ping JWP

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200819 21

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 metastatic HCC cell-derived extracellular vesicles (EVs) promotes pre-metastatic niche formation in the lung by enhancing angiogenesis and pulmonary endothelial permeability to facilitate colonization of tumor cells and extrahepatic metastasis. EV-NID1 ...[more]

PMID: 33173740

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Project description: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.