Glioblastoma hijacks microglial gene expression to support tumor growth
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/106325 https://doi.org/10.1186/s12974-020-01797-2 |
Resumo: | Background: Glioblastomas are the most common and lethal primary brain tumors. Microglia, the resident immune cells of the brain, survey their environment and respond to pathogens, toxins, and tumors. Glioblastoma cells communicate with microglia, in part by releasing extracellular vesicles (EVs). Despite the presence of large numbers of microglia in glioblastoma, the tumors continue to grow, and these neuroimmune cells appear incapable of keeping the tumor in check. To understand this process, we analyzed gene expression in microglia interacting with glioblastoma cells. Methods: We used RNASeq of isolated microglia to analyze the expression patterns of genes involved in key microglial functions in mice with glioblastoma. We focused on microglia that had taken up tumor-derived EVs and therefore were within and immediately adjacent to the tumor. Results: We show that these microglia have downregulated expression of genes involved in sensing tumor cells and tumor-derived danger signals, as well as genes used for tumor killing. In contrast, expression of genes involved in facilitating tumor spread was upregulated. These changes appear to be in part EV-mediated, since intracranial injection of EVs in normal mice led to similar transcriptional changes in microglia. We observed a similar microglial transcriptomic signature when we analyzed datasets from human patients with glioblastoma. Conclusion: Our data define a microgliaGlioblastoma specific phenotype, whereby glioblastomas have hijacked gene expression in the neuroimmune system to favor avoiding tumor sensing, suppressing the immune response, clearing a path for invasion, and enhancing tumor propagation. For further exploration, we developed an interactive online tool at http://www.glioma-microglia.com with all expression data and additional functional and pathway information for each gene. |
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Glioblastoma hijacks microglial gene expression to support tumor growthGlioblastomaGliomaMicrogliaExtracellular vesiclesExosomesMicrovesiclesMacrophagesSensomeRNASeqTGF-βAnimalsBrain NeoplasmsCell Line, TumorExtracellular VesiclesFemaleGene Knock-In TechniquesGlioblastomaMaleMiceMice, Inbred C57BLMice, TransgenicMicrogliaTumor BurdenGene Expression Regulation, NeoplasticBackground: Glioblastomas are the most common and lethal primary brain tumors. Microglia, the resident immune cells of the brain, survey their environment and respond to pathogens, toxins, and tumors. Glioblastoma cells communicate with microglia, in part by releasing extracellular vesicles (EVs). Despite the presence of large numbers of microglia in glioblastoma, the tumors continue to grow, and these neuroimmune cells appear incapable of keeping the tumor in check. To understand this process, we analyzed gene expression in microglia interacting with glioblastoma cells. Methods: We used RNASeq of isolated microglia to analyze the expression patterns of genes involved in key microglial functions in mice with glioblastoma. We focused on microglia that had taken up tumor-derived EVs and therefore were within and immediately adjacent to the tumor. Results: We show that these microglia have downregulated expression of genes involved in sensing tumor cells and tumor-derived danger signals, as well as genes used for tumor killing. In contrast, expression of genes involved in facilitating tumor spread was upregulated. These changes appear to be in part EV-mediated, since intracranial injection of EVs in normal mice led to similar transcriptional changes in microglia. We observed a similar microglial transcriptomic signature when we analyzed datasets from human patients with glioblastoma. Conclusion: Our data define a microgliaGlioblastoma specific phenotype, whereby glioblastomas have hijacked gene expression in the neuroimmune system to favor avoiding tumor sensing, suppressing the immune response, clearing a path for invasion, and enhancing tumor propagation. For further exploration, we developed an interactive online tool at http://www.glioma-microglia.com with all expression data and additional functional and pathway information for each gene.Sybren Maas acknowledges support from the Dutch Nijbakker-Morra travel stipend and the Dutch Cancer Society (KWF) travel grant. Xandra Breakefield acknowledges National Institutes of Health (NCI CA179563, CA069246 and CA232103) for funding used to perform this research. U19 CA179563 is supported by the National Institutes of Health Common Fund, through the Office of Strategic Coordination/Office of the NIH Director. Joseph El Khoury is funded by the National Institutes of Health (1RF1 AG051506, R01 AI119065). Generation of vectors used in this study was supported by the National Institutes of Health (NS045776) grant. The MGH Department of Pathology Flow and Image Cytometry Research Core obtained support from the National Institutes of Health Shared Instrumentation program (1S10OD012027-01A1, 1S10OD016372-01, 1S10RR020936-01, and 1S10RR023440-01A1)Springer Nature2020-04-16info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/106325http://hdl.handle.net/10316/106325https://doi.org/10.1186/s12974-020-01797-2eng1742-2094Maas, Sybren L. N.Abels, Erik R.Van De Haar, Lieke L.Zhang, XuanMorsett, LizaSil, SrinjoyGuedes, JoanaSen, PrithaPrabhakar, ShilpaHickman, Suzanne E.Lai, Charles P.Ting, David T.Breakefield, Xandra O.Broekman, Marike L. D.El Khoury, Josephinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-04-06T10:19:59Zoai:estudogeral.uc.pt:10316/106325Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:22:47.977969Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Glioblastoma hijacks microglial gene expression to support tumor growth |
title |
Glioblastoma hijacks microglial gene expression to support tumor growth |
spellingShingle |
Glioblastoma hijacks microglial gene expression to support tumor growth Maas, Sybren L. N. Glioblastoma Glioma Microglia Extracellular vesicles Exosomes Microvesicles Macrophages Sensome RNASeq TGF-β Animals Brain Neoplasms Cell Line, Tumor Extracellular Vesicles Female Gene Knock-In Techniques Glioblastoma Male Mice Mice, Inbred C57BL Mice, Transgenic Microglia Tumor Burden Gene Expression Regulation, Neoplastic |
title_short |
Glioblastoma hijacks microglial gene expression to support tumor growth |
title_full |
Glioblastoma hijacks microglial gene expression to support tumor growth |
title_fullStr |
Glioblastoma hijacks microglial gene expression to support tumor growth |
title_full_unstemmed |
Glioblastoma hijacks microglial gene expression to support tumor growth |
title_sort |
Glioblastoma hijacks microglial gene expression to support tumor growth |
author |
Maas, Sybren L. N. |
author_facet |
Maas, Sybren L. N. Abels, Erik R. Van De Haar, Lieke L. Zhang, Xuan Morsett, Liza Sil, Srinjoy Guedes, Joana Sen, Pritha Prabhakar, Shilpa Hickman, Suzanne E. Lai, Charles P. Ting, David T. Breakefield, Xandra O. Broekman, Marike L. D. El Khoury, Joseph |
author_role |
author |
author2 |
Abels, Erik R. Van De Haar, Lieke L. Zhang, Xuan Morsett, Liza Sil, Srinjoy Guedes, Joana Sen, Pritha Prabhakar, Shilpa Hickman, Suzanne E. Lai, Charles P. Ting, David T. Breakefield, Xandra O. Broekman, Marike L. D. El Khoury, Joseph |
author2_role |
author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Maas, Sybren L. N. Abels, Erik R. Van De Haar, Lieke L. Zhang, Xuan Morsett, Liza Sil, Srinjoy Guedes, Joana Sen, Pritha Prabhakar, Shilpa Hickman, Suzanne E. Lai, Charles P. Ting, David T. Breakefield, Xandra O. Broekman, Marike L. D. El Khoury, Joseph |
dc.subject.por.fl_str_mv |
Glioblastoma Glioma Microglia Extracellular vesicles Exosomes Microvesicles Macrophages Sensome RNASeq TGF-β Animals Brain Neoplasms Cell Line, Tumor Extracellular Vesicles Female Gene Knock-In Techniques Glioblastoma Male Mice Mice, Inbred C57BL Mice, Transgenic Microglia Tumor Burden Gene Expression Regulation, Neoplastic |
topic |
Glioblastoma Glioma Microglia Extracellular vesicles Exosomes Microvesicles Macrophages Sensome RNASeq TGF-β Animals Brain Neoplasms Cell Line, Tumor Extracellular Vesicles Female Gene Knock-In Techniques Glioblastoma Male Mice Mice, Inbred C57BL Mice, Transgenic Microglia Tumor Burden Gene Expression Regulation, Neoplastic |
description |
Background: Glioblastomas are the most common and lethal primary brain tumors. Microglia, the resident immune cells of the brain, survey their environment and respond to pathogens, toxins, and tumors. Glioblastoma cells communicate with microglia, in part by releasing extracellular vesicles (EVs). Despite the presence of large numbers of microglia in glioblastoma, the tumors continue to grow, and these neuroimmune cells appear incapable of keeping the tumor in check. To understand this process, we analyzed gene expression in microglia interacting with glioblastoma cells. Methods: We used RNASeq of isolated microglia to analyze the expression patterns of genes involved in key microglial functions in mice with glioblastoma. We focused on microglia that had taken up tumor-derived EVs and therefore were within and immediately adjacent to the tumor. Results: We show that these microglia have downregulated expression of genes involved in sensing tumor cells and tumor-derived danger signals, as well as genes used for tumor killing. In contrast, expression of genes involved in facilitating tumor spread was upregulated. These changes appear to be in part EV-mediated, since intracranial injection of EVs in normal mice led to similar transcriptional changes in microglia. We observed a similar microglial transcriptomic signature when we analyzed datasets from human patients with glioblastoma. Conclusion: Our data define a microgliaGlioblastoma specific phenotype, whereby glioblastomas have hijacked gene expression in the neuroimmune system to favor avoiding tumor sensing, suppressing the immune response, clearing a path for invasion, and enhancing tumor propagation. For further exploration, we developed an interactive online tool at http://www.glioma-microglia.com with all expression data and additional functional and pathway information for each gene. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-04-16 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/106325 http://hdl.handle.net/10316/106325 https://doi.org/10.1186/s12974-020-01797-2 |
url |
http://hdl.handle.net/10316/106325 https://doi.org/10.1186/s12974-020-01797-2 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1742-2094 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Springer Nature |
publisher.none.fl_str_mv |
Springer Nature |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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