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Hepato-entrained B220+CD11c+NK1.1+ cells regulate pre-metastatic niche formation in the lung

ABSTRACT: Primary tumours establish metastases by interfering with distinct organs. In pre-metastatic organs, a tumour-friendly microenvironment supports metastatic cells, and is prepared by many factors including tissue resident cells, bone marrow-derived cells and abundant fibrinogen depositions. However, other components are unclear. Here we show that a third organ, originally regarded as a bystander, plays an important role in metastasis by directly affecting the pre-metastatic soil. In our model system, the liver participated in lung metastasis as a leukocyte supplier. These liver-derived leukocytes displayed liver-like characteristics and, thus, were designated hepato-entrained leukocytes (HepELs). HepELs had high expression levels of coagulation factor X (FX) and vitronectin (Vtn), and relocated to fibrinogen-rich hyperpermeable regions in pre-metastatic lungs; the cells then switched their expression from Vtn to thrombospondin, both of which were fibrinogen-binding proteins. Cell surface marker analysis revealed that HepELs contained B220+CD11c+NK1.1+ cells. In addition, an injection of B220+CD11c+NK1.1+ cells successfully eliminated fibrinogen depositions in pre-metastatic lungs via FX. Moreover, B220+CD11c+NK1.1+ cells demonstrated anti-metastatic tumour ability with IFNγ induction. These findings indicate that liver-primed B220+CD11c+NK1.1+ cells suppress lung metastasis.

SUBMITTER: Dr. Sachie Hiratsuka

PROVIDER: S-SCDT-EMM-2017-08643 | biostudies-other |

REPOSITORIES: biostudies-other

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Hepato-entrained B220+CD11c+NK1.1+ cells regulate pre-metastatic niche formation in the lung.

Project description:Primary tumours establish metastases by interfering with distinct organs. In pre-metastatic organs, a tumour-friendly microenvironment supports metastatic cells and is prepared by many factors including tissue resident cells, bone marrow-derived cells and abundant fibrinogen depositions. However, other components are unclear. Here, we show that a third organ, originally regarded as a bystander, plays an important role in metastasis by directly affecting the pre-metastatic soil. In our model system, the liver participated in lung metastasis as a leucocyte supplier. These liver-derived leucocytes displayed liver-like characteristics and, thus, were designated hepato-entrained leucocytes (HepELs). HepELs had high expression levels of coagulation factor X (FX) and vitronectin (Vtn) and relocated to fibrinogen-rich hyperpermeable regions in pre-metastatic lungs; the cells then switched their expression from Vtn to thrombospondin, both of which were fibrinogen-binding proteins. Cell surface marker analysis revealed that HepELs contained B220+CD11c+NK1.1+ cells. In addition, an injection of B220+CD11c+NK1.1+ cells successfully eliminated fibrinogen depositions in pre-metastatic lungs via FX Moreover, B220+CD11c+NK1.1+ cells demonstrated anti-metastatic tumour ability with IFNγ induction. These findings indicate that liver-primed B220+CD11c+NK1.1+ cells suppress lung metastasis.

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Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment.

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HAO1-mediated oxalate metabolism promotes lung pre-metastatic niche formation by inducing neutrophil extracellular traps.

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Tumor-derived Cav-1 promotes pre-metastatic niche formation and lung metastasis in breast cancer.

Project description:Rationale: Breast cancer (BC), as one of the most frequently diagnosed cancer, has a poor prognosis due to the development of distant metastasis. Among the BC metastatic sites, lung is one of the most common sites. Caveolin-1 (Cav-1) is a functional membrane protein that plays a vital role in tumor metastasis. Although studies have revealed that Cav-1 levels were elevated in patients with advanced cancer, whether Cav-1 affects BC lung metastasis by influencing the formation of pre-metastatic niche (PMN) through exosomes has not been explored. Methods: Differential ultracentrifugation, transmission electron microscopy and nanoparticle tracking analysis were used to verify the presence of exosomes. Transwell assays were used to examine the biological effects of exosomes containing Cav-1. Both in vitro cell cultures and mammary tumor cell-induced mouse models were used to assess the lung metastasis. The regulatory mechanisms of PMN formation were revealed using western blot, flow cytometry, RT-qPCR, immunofluorescence assays, gene overexpression assays and RNA interference assays. Results: Exosomes have critical functions in transporting Cav-1 between primary BC and metastatic organ microenvironments. Cav-1 in BC-derived exosomes can act as a signaling molecule to mediate intercellular communication and regulate the PMN before lung metastasis by regulating the expression of PMN marker genes and inflammatory chemokines in lung epithelial cells, promoting the secretion of tenascin-C (TnC) in lung fibroblasts to cause extracellular matrix (ECM) deposition, and inhibiting the PTEN/CCL2/VEGF-A signaling pathway in lung macrophages to facilitate their M2-type polarization and angiogenesis. Conclusion: Our study investigated the mechanisms of lung PMN formation induced by Cav-1 in BC-derived exosomes. Our data may provide new directions for exploring the mechanisms and developing treatment strategies of BC lung metastasis.

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Project description:Lymph node metastasis is a crucial prognostic parameter in many different types of cancers and a gateway for further dissemination to distant organs. Prior to metastatic dissemination, the primary tumor prepares for the remodeling of the draining (sentinel) lymph node by secreting soluble factors or releasing extracellular vesicles that are transported by lymphatic vessels. These important changes occur before the appearance of the first metastatic cell and create what is known as a pre-metastatic niche giving rise to the subsequent survival and growth of metastatic cells. In this review, the lymph node structure, matrix composition and the emerging heterogeneity of cells forming it are described. Current knowledge of the major cellular and molecular processes associated with nodal pre-metastatic niche formation, including lymphangiogenesis, extracellular matrix remodeling, and immunosuppressive cell enlisting in lymph nodes are additionally summarized. Finally, future directions that research could possibly take and the clinical impact are discussed.

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