Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET.
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 permane...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2012 |
| País: | España |
| Institución: | Instituto de Salud Carlos III (ISCIII) |
| Repositorio: | Repisalud |
| Idioma: | inglés |
| OAI Identifier: | oai:repisalud.isciii.es:20.500.12105/17965 |
| Acceso en línea: | http://hdl.handle.net/20.500.12105/17965 |
| Access Level: | acceso abierto |
| Palabra clave: | Animals Bone Marrow Cells Cell Line Exosomes Female Humans Melanoma Mice Mice, Inbred C57BL Phenotype Prognosis Proto-Oncogene Proteins c-met Stem Cells rab GTP-Binding Proteins rab27 GTP-Binding Proteins |
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Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET.Peinado, HéctorAlečković, MašaLavotshkin, SimonMatei, IrinaCosta-Silva, BrunoMoreno-Bueno, GemaHergueta-Redondo, MartaWilliams, CaitlinGarcía-Santos, GuillermoGhajar, CyrusNitadori-Hoshino, AyukoHoffman, CaitlinBadal, KarenGarcia, Benjamin ACallahan, Margaret KYuan, JiandaMartins, Vilma RSkog, JohanKaplan, Rosandra NBrady, Mary SWolchok, Jedd DChapman, Paul BKang, YibinBromberg, JacquelineLyden, DavidAnimalsBone Marrow CellsCell LineExosomesFemaleHumansMelanomaMiceMice, Inbred C57BLPhenotypePrognosisProto-Oncogene Proteins c-metStem Cellsrab GTP-Binding Proteinsrab27 GTP-Binding ProteinsTumor-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 'educating' 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.Nature Publishing Group20242024-02-1220122012-06-0120122012-06-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.12105/17965reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/179652026-06-12T12:43:37Z |
| dc.title.none.fl_str_mv |
Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. |
| title |
Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. |
| spellingShingle |
Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Peinado, Héctor Animals Bone Marrow Cells Cell Line Exosomes Female Humans Melanoma Mice Mice, Inbred C57BL Phenotype Prognosis Proto-Oncogene Proteins c-met Stem Cells rab GTP-Binding Proteins rab27 GTP-Binding Proteins |
| title_short |
Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. |
| title_full |
Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. |
| title_fullStr |
Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. |
| title_full_unstemmed |
Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. |
| title_sort |
Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. |
| dc.creator.none.fl_str_mv |
Peinado, Héctor Alečković, Maša Lavotshkin, Simon Matei, Irina Costa-Silva, Bruno Moreno-Bueno, Gema Hergueta-Redondo, Marta Williams, Caitlin García-Santos, Guillermo Ghajar, Cyrus Nitadori-Hoshino, Ayuko Hoffman, Caitlin Badal, Karen Garcia, Benjamin A Callahan, Margaret K Yuan, Jianda Martins, Vilma R Skog, Johan Kaplan, Rosandra N Brady, Mary S Wolchok, Jedd D Chapman, Paul B Kang, Yibin Bromberg, Jacqueline Lyden, David |
| author |
Peinado, Héctor |
| author_facet |
Peinado, Héctor Alečković, Maša Lavotshkin, Simon Matei, Irina Costa-Silva, Bruno Moreno-Bueno, Gema Hergueta-Redondo, Marta Williams, Caitlin García-Santos, Guillermo Ghajar, Cyrus Nitadori-Hoshino, Ayuko Hoffman, Caitlin Badal, Karen Garcia, Benjamin A Callahan, Margaret K Yuan, Jianda Martins, Vilma R Skog, Johan Kaplan, Rosandra N Brady, Mary S Wolchok, Jedd D Chapman, Paul B Kang, Yibin Bromberg, Jacqueline Lyden, David |
| author_role |
author |
| author2 |
Alečković, Maša Lavotshkin, Simon Matei, Irina Costa-Silva, Bruno Moreno-Bueno, Gema Hergueta-Redondo, Marta Williams, Caitlin García-Santos, Guillermo Ghajar, Cyrus Nitadori-Hoshino, Ayuko Hoffman, Caitlin Badal, Karen Garcia, Benjamin A Callahan, Margaret K Yuan, Jianda Martins, Vilma R Skog, Johan Kaplan, Rosandra N Brady, Mary S Wolchok, Jedd D Chapman, Paul B Kang, Yibin Bromberg, Jacqueline Lyden, David |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
|
| dc.subject.none.fl_str_mv |
Animals Bone Marrow Cells Cell Line Exosomes Female Humans Melanoma Mice Mice, Inbred C57BL Phenotype Prognosis Proto-Oncogene Proteins c-met Stem Cells rab GTP-Binding Proteins rab27 GTP-Binding Proteins |
| topic |
Animals Bone Marrow Cells Cell Line Exosomes Female Humans Melanoma Mice Mice, Inbred C57BL Phenotype Prognosis Proto-Oncogene Proteins c-met Stem Cells rab GTP-Binding Proteins rab27 GTP-Binding Proteins |
| description |
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 'educating' 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. |
| publishDate |
2012 |
| dc.date.none.fl_str_mv |
2012 2012-06-01 2012 2012-06-01 2024 2024-02-12 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/20.500.12105/17965 |
| url |
http://hdl.handle.net/20.500.12105/17965 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
Nature Publishing Group |
| publisher.none.fl_str_mv |
Nature Publishing Group |
| dc.source.none.fl_str_mv |
reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII) |
| instname_str |
Instituto de Salud Carlos III (ISCIII) |
| reponame_str |
Repisalud |
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Repisalud |
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|
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1869419777410203648 |
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15,811543 |