Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis

Nat Cell Biol. 2019 Nov;21(11):1403-1412. doi: 10.1038/s41556-019-0404-4. Epub 2019 Nov 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

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