Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis.

TitleTumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis.
Publication TypeJournal Article
Year of Publication2019
AuthorsRodrigues G, Hoshino A, Kenific CM, Matei IR, Steiner L, Freitas D, Kim HSang, Oxley PR, Scandariato I, Casanova-Salas I, Dai J, Badwe CR, Gril B, Mark MTesic, 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 SEmily, Rafii S, Altorki NKhaled, Rudin CM, Jones DR, Steeg PS, Peinado H, Ghajar CM, Bromberg JF, de Sousa M, Pisapia DJ, Lyden DC
JournalNat Cell Biol
Date Published2019 11
KeywordsAnimals, Brain, Brain Neoplasms, Cell Line, Tumor, Cell Movement, Cell Proliferation, Chemokine CCL1, Chemokine CXCL1, Cyclooxygenase 2, Endothelial Cells, Exosomes, Gene Expression Regulation, Neoplastic, Humans, Hyaluronoglucosaminidase, Mice, Mice, Inbred C57BL, Mice, Nude, Neoplasm Metastasis, Neovascularization, Pathologic, Signal Transduction, Survival Analysis, Tumor Burden, Tumor Microenvironment, Tumor Necrosis Factor-alpha, Xenograft Model Antitumor Assays

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.

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Alternate JournalNat. Cell Biol.
PubMed ID31685984
PubMed Central IDPMC7354005
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R35 CA232093 / CA / NCI NIH HHS / United States
U01 CA169538 / CA / NCI NIH HHS / United States
U54 CA193461 / CA / NCI NIH HHS / United States

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