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Tumour Exosomal CEMIP Protein Promotes Cancer Cell Colonization in Brain Metastasis

Authors
 Gonçalo Rodrigues  ;  Ayuko Hoshino  ;  Candia M Kenific  ;  Irina R Matei  ;  Loïc Steiner  ;  Daniela Freitas  ;  Han Sang Kim  ;  Peter R Oxley  ;  Ilana Scandariato  ;  Irene Casanova-Salas  ;  Jinxiang Dai  ;  Chaitanya R Badwe  ;  Brunilde Gril  ;  Milica Tešić Mark  ;  Brian D Dill  ;  Henrik Molina  ;  Haiying Zhang  ;  Alberto Benito-Martin  ;  Linda Bojmar  ;  Yonathan Ararso  ;  Katharine Offer  ;  Quincey LaPlant  ;  Weston Buehring  ;  Huajuan Wang  ;  Xinran Jiang  ;  Tyler M Lu  ;  Yuan Liu  ;  Joshua K Sabari  ;  Sandra J Shin  ;  Navneet Narula  ;  Paula S Ginter  ;  Vinagolu K Rajasekhar  ;  John H Healey  ;  Etienne Meylan  ;  Bruno Costa-Silva  ;  Shizhen Emily Wang  ;  Shahin Rafii  ;  Nasser Khaled Altorki  ;  Charles M Rudin  ;  David R Jones  ;  Patricia S Steeg  ;  Héctor Peinado  ;  Cyrus M Ghajar  ;  Jacqueline Bromberg  ;  Maria de Sousa  ;  David Pisapia  ;  David Lyden 
Citation
 NATURE CELL BIOLOGY, Vol.21(11) : 1403-1412, 2019-11 
Journal Title
 NATURE CELL BIOLOGY 
ISSN
 1465-7392 
Issue Date
2019-11
MeSH
Animals ; Brain / metabolism ; Brain / pathology ; Brain Neoplasms / genetics* ; 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 / metabolism* ; Exosomes / pathology ; Gene Expression Regulation, Neoplastic* ; Humans ; Hyaluronoglucosaminidase / genetics* ; Hyaluronoglucosaminidase / metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Neoplasm Metastasis ; Neovascularization, Pathologic / genetics* ; Neovascularization, Pathologic / metabolism ; Neovascularization, Pathologic / mortality ; Neovascularization, Pathologic / pathology ; Signal Transduction ; Survival Analysis ; Tumor Burden ; Tumor Microenvironment / genetics* ; Tumor Necrosis Factor-alpha / genetics ; Tumor Necrosis Factor-alpha / metabolism ; Xenograft Model Antitumor Assays
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.
Full Text
https://www.nature.com/articles/s41556-019-0404-4
DOI
10.1038/s41556-019-0404-4
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Han Sang(김한상) ORCID logo https://orcid.org/0000-0002-6504-9927
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/175873
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