1. Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis.
- Author
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Rodrigues G, Hoshino A, Kenific CM, Matei IR, Steiner L, Freitas D, Kim HS, Oxley PR, Scandariato I, Casanova-Salas I, Dai J, Badwe CR, Gril B, Tešić Mark M, Dill BD, Molina H, Zhang H, Benito-Martin A, Bojmar L, Ararso Y, Offer K, LaPlant Q, Buehring W, Wang H, Jiang X, Lu TM, Liu Y, Sabari JK, Shin SJ, Narula N, Ginter PS, Rajasekhar VK, Healey JH, Meylan E, Costa-Silva B, Wang SE, Rafii S, Altorki NK, Rudin CM, Jones DR, Steeg PS, Peinado H, Ghajar CM, Bromberg J, de Sousa M, Pisapia D, and Lyden D
- Subjects
- Animals, Brain metabolism, Brain pathology, Brain Neoplasms metabolism, Brain Neoplasms mortality, Brain Neoplasms pathology, Cell Line, Tumor, Cell Movement, Cell Proliferation, Chemokine CCL1 genetics, Chemokine CCL1 metabolism, Chemokine CXCL1 genetics, Chemokine CXCL1 metabolism, Cyclooxygenase 2 genetics, Cyclooxygenase 2 metabolism, Endothelial Cells metabolism, Endothelial Cells pathology, Exosomes pathology, Humans, Hyaluronoglucosaminidase metabolism, Mice, Mice, Inbred C57BL, Mice, Nude, Neoplasm Metastasis, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic mortality, Neovascularization, Pathologic pathology, Signal Transduction, Survival Analysis, Tumor Burden, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Xenograft Model Antitumor Assays, Brain Neoplasms genetics, Exosomes metabolism, Gene Expression Regulation, Neoplastic, Hyaluronoglucosaminidase genetics, Neovascularization, Pathologic genetics, Tumor Microenvironment genetics
- Abstract
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.- Published
- 2019
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