@article{88206,
  keywords = {Animals, Humans, Cell Line, Phenotype, Mice, Mice, Inbred C57BL, Female, Prognosis, rab GTP-Binding Proteins, Stem Cells, Bone Marrow Cells, Exosomes, Melanoma, Proto-Oncogene Proteins c-met},
  author = {H{\'e}ctor Peinado and Ma{\v s}a Ale{\v c}kovi{\'c} and Simon Lavotshkin and Irina Matei and Bruno Costa-Silva and Gema Moreno-Bueno and Marta Hergueta-Redondo and Caitlin Williams and Guillermo Garc{\'\i}a-Santos and Cyrus Ghajar and Ayuko Nitadori-Hoshino and Caitlin Hoffman and Karen Badal and Benjamin Garcia and Margaret Callahan and Jianda Yuan and Vilma Martins and Johan Skog and Rosandra Kaplan and Mary Brady and Jedd Wolchok and Paul Chapman and Yibin Kang and Jacqueline Bromberg and David Lyden},
  title = {Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET.},
  abstract = {<p>Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently {\textquoteright}educating{\textquoteright} bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.</p>
},
  year = {2012},
  journal = {Nat Med},
  volume = {18},
  pages = {883-91},
  month = {06/2012},
  issn = {1546-170X},
  doi = {10.1038/nm.2753},
  language = {eng},
}