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.
Bibliographical noteFunding Information:
We thank M. Ginsberg, G. Marra, P. Raju and T. Milner for reagents and expert advice; L. Nogues Vera, M. Teixeira and S. Grass for help in the laboratory; M. Schaeffer for proofreading; T. Zhang and K. Gyan for help with bioinformatics analysis; L. Cohen-Gould, the MSKCC Molecular Cytology Core Facility and K. Uryu for imaging counselling; T. Miller and F. Fang at the MSKCC Flow cytometry Core Facility, and T. Baumgartner at the Weill Cornell Medicine Flow Cytometry Core, as well as R. Bowman, for expert cell sorting; and the MSKCC Gene Editing and Screening Core Facility for molecular cloning and gene editing advice. We gratefully acknowledge support from the following funding sources: the National Cancer Institute (CA169538 to D.L. and CA232093 to D.L.), the US Department of Defense (W81XWH-13-1-0427 to D.L.), the Breast Cancer Research Foundation (to D.L. and C.M.G.), the Champalimaud Foundation, the Daedalus Fund for Innovation (Weill Cornell Medicine, to D.L.), the Children’s Cancer and Blood Foundation, the Pediatric Oncology Experimental Therapeutics Investigator’s Consortium Foundation, the Nancy C. and Daniel P. Paduano Foundation, the Eileen and James A. Paduano Foundation, the Sohn Foundation, the Hartwell Foundation, the Manning Foundation, the Thompson Foundation, the Malcolm Hewitt Wiener Foundation and the Tortolani Foundation. G.R. has been supported by a Peter Oppenheimer Fellowship, awarded by the American Portuguese Biomedical Research Fund, and by the Fundação para a Ciência e a Tecnologia from Portugal. A.H. was supported by a Susan Komen Foundation for the Cure Fellowship. H.P. is supported by grants from MINECO (SAF2014-54541-R), Fundación Fero, Asociación Española Contra el Cáncer and Worldwide Cancer Research. C.M.G. is supported by a US Department of Defense Breast Cancer Research Program Era of Hope Scholar Award (W81XWH-15-1-0201), the US National Cancer Institute (CA193461-01), the National Breast Cancer Coalition’s Artemis Project and the Pink Gene Foundation.
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
All Science Journal Classification (ASJC) codes
- Cell Biology