Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis
Copyright policy )Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis
The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.
- Institute of Science Tokyo Japan
- National Presto Industries United States
- Fred Hutchinson Cancer Research Center United States
- Universidade Lusófona do Porto Portugal
- Université Libre de Bruxelles Belgium
Chemokine CXCL1, Nude, Brain Neoplasms / metabolism, Inbred C57BL, Exosomes, Medical and Health Sciences, ANGIOGENESIS, Hyaluronoglucosaminidase / genetics*, Chemokine CCL1, Mice, Pathologic / metabolism, Brain Neoplasms / pathology, Cell Movement, Chemokine CXCL1 / genetics, Tumor Necrosis Factor-alpha / metabolism, Tumor Microenvironment, 2.1 Biological and endogenous factors, Neoplastic*, Pathologic / pathology, Aetiology, Neoplasm Metastasis, Cancer, KIAA1199, Tumor, Neovascularization, Pathologic, Endothelial Cells / metabolism, Brain Neoplasms, Brain / pathology, Brain, Sciences bio-médicales et agricoles, Biological Sciences, Cyclooxygenase 2 / genetics, Tumor Burden, Gene Expression Regulation, Neoplastic, GROWTH, Brain / metabolism, Hyaluronoglucosaminidase / metabolism, Chemokine CCL1 / metabolism, Signal Transduction, Tumor Necrosis Factor-alpha / genetics, 610, Hyaluronoglucosaminidase, Mice, Nude, Exosomes / metabolism*, Chemokine CCL1 / genetics, Tumor Microenvironment / genetics*, Cell Line, Rare Diseases, Pathologic / mortality, Cell Line, Tumor, Brain Neoplasms / mortality, Animals, Humans, Neovascularization, Cell Proliferation, Pathologic, Neoplastic, Cyclooxygenase 2 / metabolism, Tumor Necrosis Factor-alpha, Neurosciences, EXTRACELLULAR VESICLES, Endothelial Cells, Brain Neoplasms / genetics*, Pathologic / genetics*, Survival Analysis, Xenograft Model Antitumor Assays, GENE, Mice, Inbred C57BL, Gene Expression Regulation, Cyclooxygenase 2, Biochemistry and cell biology, Exosomes / pathology, Endothelial Cells / pathology, Chemokine CXCL1 / metabolism, Biochemistry and Cell Biology, Developmental Biology
Chemokine CXCL1, Nude, Brain Neoplasms / metabolism, Inbred C57BL, Exosomes, Medical and Health Sciences, ANGIOGENESIS, Hyaluronoglucosaminidase / genetics*, Chemokine CCL1, Mice, Pathologic / metabolism, Brain Neoplasms / pathology, Cell Movement, Chemokine CXCL1 / genetics, Tumor Necrosis Factor-alpha / metabolism, Tumor Microenvironment, 2.1 Biological and endogenous factors, Neoplastic*, Pathologic / pathology, Aetiology, Neoplasm Metastasis, Cancer, KIAA1199, Tumor, Neovascularization, Pathologic, Endothelial Cells / metabolism, Brain Neoplasms, Brain / pathology, Brain, Sciences bio-médicales et agricoles, Biological Sciences, Cyclooxygenase 2 / genetics, Tumor Burden, Gene Expression Regulation, Neoplastic, GROWTH, Brain / metabolism, Hyaluronoglucosaminidase / metabolism, Chemokine CCL1 / metabolism, Signal Transduction, Tumor Necrosis Factor-alpha / genetics, 610, Hyaluronoglucosaminidase, Mice, Nude, Exosomes / metabolism*, Chemokine CCL1 / genetics, Tumor Microenvironment / genetics*, Cell Line, Rare Diseases, Pathologic / mortality, Cell Line, Tumor, Brain Neoplasms / mortality, Animals, Humans, Neovascularization, Cell Proliferation, Pathologic, Neoplastic, Cyclooxygenase 2 / metabolism, Tumor Necrosis Factor-alpha, Neurosciences, EXTRACELLULAR VESICLES, Endothelial Cells, Brain Neoplasms / genetics*, Pathologic / genetics*, Survival Analysis, Xenograft Model Antitumor Assays, GENE, Mice, Inbred C57BL, Gene Expression Regulation, Cyclooxygenase 2, Biochemistry and cell biology, Exosomes / pathology, Endothelial Cells / pathology, Chemokine CXCL1 / metabolism, Biochemistry and Cell Biology, Developmental Biology
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