Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis Journal Article
| Authors: | Rodrigues, G.; Hoshino, A.; Kenific, C. M.; Matei, I. R.; Steiner, L.; Freitas, D.; Kim, H. S.; Oxley, P. R.; Scandariato, I.; Casanova-Salas, I.; Dai, J.; Badwe, C. R.; Gril, B.; Tešić Mark, M.; Dill, B. D.; Molina, H.; Zhang, H.; Benito-Martin, A.; Bojmar, L.; Ararso, Y.; Offer, K.; LaPlant, Q.; Buehring, W.; Wang, H.; Jiang, X.; Lu, T. M.; Liu, Y.; Sabari, J. K.; Shin, S. J.; Narula, N.; Ginter, P. S.; Rajasekhar, V. K.; Healey, J. H.; Meylan, E.; Costa-Silva, B.; Wang, S. E.; Rafii, S.; Altorki, N. K.; Rudin, C. M.; Jones, D. R.; Steeg, P. S.; Peinado, H.; Ghajar, C. M.; Bromberg, J.; de Sousa, M.; Pisapia, D.; Lyden, D. |
| Article Title: | 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. © 2019, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | adult; cancer survival; controlled study; human tissue; unclassified drug; human cell; nonhuman; bone metastasis; protein function; animal cell; mouse; phenotype; animal tissue; protein depletion; cell protein; animal experiment; inflammation; cohort analysis; proteomics; prediction; endothelium cell; lung metastasis; cytokine; cancer cell; brain metastasis; cellular distribution; binding protein; upregulation; cancer tissue; brain blood vessel; tnf gene; cell invasion; tumor necrosis factor; tumor microenvironment; microglia; exosome; brain cell; human; female; priority journal; article; cell migration inducing and hyaluronan binding protein; ccl gene; cxcl gene; ptgs2 gene |
| Journal Title: | Nature Cell Biology |
| Volume: | 21 |
| Issue: | 11 |
| ISSN: | 1465-7392 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2019-11-01 |
| Start Page: | 1403 |
| End Page: | 1412 |
| Language: | English |
| DOI: | 10.1038/s41556-019-0404-4 |
| PUBMED: | 31685984 |
| PROVIDER: | scopus |
| PMCID: | PMC7354005 |
| DOI/URL: | |
| Notes: | Rajasekhar Vinagolu's first and last names are reversed on the original publication -- Article -- Source: Scopus |
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