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oai:repisalud.isciii.es:20.500.12105/259602025-12-18T12:53:39Zcom_20.500.12105_2273com_20.500.12105_2202col_20.500.12105_19571

00925njm 22002777a 4500 dc Rodrigues, Gonçalo author Hoshino, Ayuko author Kenific, Candia M author Matei, Irina R author Steiner, Loïc author Freitas, Daniela author Kim, Han Sang author Oxley, Peter R author Scandariato, Ilana author Casanova-Salas, Irene author Dai, Jinxiang author Badwe, Chaitanya R author Gril, Brunilde author Tešić Mark, Milica author Dill, Brian D author Molina, Henrik author Zhang, Haiying author Benito-Martin, Alberto author Bojmar, Linda author Ararso, Yonathan author Offer, Katharine author LaPlant, Quincey author Buehring, Weston author Wang, Huajuan author Jiang, Xinran author Lu, Tyler M author Liu, Yuan author Sabari, Joshua K author Shin, Sandra J author Narula, Navneet author Ginter, Paula S author Rajasekhar, Vinagolu K author Healey, John H author Meylan, Etienne author Costa-Silva, Bruno author Wang, Shizhen Emily author Rafii, Shahin author Altorki, Nasser Khaled author Rudin, Charles M author Jones, David R author Steeg, Patricia S author Peinado Selgas, Hector author Ghajar, Cyrus M author Bromberg, Jacqueline author de Sousa, Maria author Pisapia, David author Lyden, David author 2019-11 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. Nature Cell Biology https://pmc.ncbi.nlm.nih.gov/articles/PMC7354005/pdf/nihms-1604880.pdf 31685984 https://hdl.handle.net/20.500.12105/25960 EXTRACELLULAR VESICLES KIAA1199 ANGIOGENESIS GROWTH GENE Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis.