Journal
NATURE CELL BIOLOGY
Volume 21, Issue 11, Pages 1403-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-019-0404-4
Keywords
-
Categories
Funding
- National Cancer Institute [CA169538, CA232093]
- US Department of Defense [W81XWH-13-1-0427]
- Breast Cancer Research Foundation
- Champalimaud Foundation
- Daedalus Fund for Innovation (Weill Cornell Medicine)
- Children's Cancer and Blood Foundation
- Pediatric Oncology Experimental Therapeutics Investigator's Consortium Foundation
- Nancy C. and Daniel P. Paduano Foundation
- Eileen and James A. Paduano Foundation
- Sohn Foundation
- Manning Foundation
- Thompson Foundation
- Malcolm Hewitt Wiener Foundation
- Tortolani Foundation
- Hartwell Foundation
- Peter Oppenheimer Fellowship - American Portuguese Biomedical Research Fund
- Fundacao para a Ciencia e a Tecnologia from Portugal
- Susan Komen Foundation for the Cure Fellowship
- MINECO [SAF2014-54541-R]
- Fundacion Fero
- US Department of Defense Breast Cancer Research Program Era of Hope Scholar Award [W81XWH-15-1-0201]
- US National Cancer Institute [CA193461-01]
- National Breast Cancer Coalition's Artemis Project
- Pink Gene Foundation
- Asociacion Espanola Contra el Cancer
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available