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


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.

SUBMITTER: Rodrigues G 

PROVIDER: S-EPMC7354005 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Rodrigues Gonçalo G   Hoshino Ayuko A   Kenific Candia M CM   Matei Irina R IR   Steiner Loïc L   Freitas Daniela D   Kim Han Sang HS   Oxley Peter R PR   Scandariato Ilana I   Casanova-Salas Irene I   Dai Jinxiang J   Badwe Chaitanya R CR   Gril Brunilde B   Tešić Mark Milica M   Dill Brian D BD   Molina Henrik H   Zhang Haiying H   Benito-Martin Alberto A   Bojmar Linda L   Ararso Yonathan Y   Offer Katharine K   LaPlant Quincey Q   Buehring Weston W   Wang Huajuan H   Jiang Xinran X   Lu Tyler M TM   Liu Yuan Y   Sabari Joshua K JK   Shin Sandra J SJ   Narula Navneet N   Ginter Paula S PS   Rajasekhar Vinagolu K VK   Healey John H JH   Meylan Etienne E   Costa-Silva Bruno B   Wang Shizhen Emily SE   Rafii Shahin S   Altorki Nasser Khaled NK   Rudin Charles M CM   Jones David R DR   Steeg Patricia S PS   Peinado Héctor H   Ghajar Cyrus M CM   Bromberg Jacqueline J   de Sousa Maria M   Pisapia David D   Lyden David D  

Nature cell biology 20191104 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  ...[more]

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