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.

• 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
• Journal: Nature cell biology (Nat Cell Biol) Vol. 21 Issue 11 Pg. 1403-1412 (11 2019) ISSN: 1476-4679 [Electronic] England
• PMID: 31685984 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CCL1 protein, human
• CXCL1 protein, human
• Chemokine CCL1
• Chemokine CXCL1
• Tumor Necrosis Factor-alpha
• Cyclooxygenase 2
• PTGS2 protein, human
• CEMIP protein, human
• Hyaluronoglucosaminidase

Topics

• Animals
• Brain (metabolism, pathology)
• Brain Neoplasms (genetics, metabolism, mortality, pathology)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Chemokine CCL1 (genetics, metabolism)
• Chemokine CXCL1 (genetics, metabolism)
• Cyclooxygenase 2 (genetics, metabolism)
• Endothelial Cells (metabolism, pathology)
• Exosomes (metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• Hyaluronoglucosaminidase (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Neoplasm Metastasis
• Neovascularization, Pathologic (genetics, metabolism, mortality, pathology)
• Signal Transduction
• Survival Analysis
• Tumor Burden
• Tumor Microenvironment (genetics)
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• Xenograft Model Antitumor Assays