Single‐cell RNA sequencing reveals tumor heterogeneity, microenvironment, and drug‐resistance mechanisms of recurrent glioblastoma
Glioblastomas are highly heterogeneous brain tumors. Despite the availability of standard treatment for glioblastoma multiforme (GBM), i.e., Stupp protocol, which involves surgical resection followed by radiotherapy and chemotherapy, glioblastoma remains refractory to treatment and recurrence is ine...
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description | Glioblastomas are highly heterogeneous brain tumors. Despite the availability of standard treatment for glioblastoma multiforme (GBM), i.e., Stupp protocol, which involves surgical resection followed by radiotherapy and chemotherapy, glioblastoma remains refractory to treatment and recurrence is inevitable. Moreover, the biology of recurrent glioblastoma remains unclear. Increasing evidence has shown that intratumoral heterogeneity and the tumor microenvironment contribute to therapeutic resistance. However, the interaction between intracellular heterogeneity and drug resistance in recurrent GBMs remains controversial. The aim of this study was to map the transcriptome landscape of cancer cells and the tumor heterogeneity and tumor microenvironment in recurrent and drug‐resistant GBMs at a single‐cell resolution and further explore the mechanism of drug resistance of GBMs. We analyzed six tumor tissue samples from three patients with primary GBM and three patients with recurrent GBM in which recurrence and drug resistance developed after treatment with the standard Stupp protocol using single‐cell RNA sequencing. Using unbiased clustering, nine major cell clusters were identified. Upregulation of the expression of stemness‐related and cell‐cycle‐related genes was observed in recurrent GBM cells. Compared with the initial GBM tissues, recurrent GBM tissues showed a decreased proportion of microglia, consistent with previous reports. Finally, vascular endothelial growth factor A expression and the blood–brain barrier permeability were high, and the O6‐methylguanine DNA methyltransferase‐related signaling pathway was activated in recurrent GBM. Our results delineate the single‐cell map of recurrent glioblastoma, tumor heterogeneity, tumor microenvironment, and drug‐resistance mechanisms, providing new insights into treatment strategies for recurrent glioblastomas.
We observed upregulation of the expression of stemness‐related and cell‐cycle‐related genes in recurrent GBM cells. Further, we observed that recurrent GBM tissues showed a decreased proportion of microglia, consistent with previous reports, and that vascular endothelial growth factor A expression and the blood–brain barrier permeability were high, and the O6‐methylguanine DNA methyltransferase‐related signaling pathway was activated in recurrent GBM. Our results provide new insights into treatment strategies for recurrent glioblastomas. |
doi_str_mv | 10.1111/cas.15773 |
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We observed upregulation of the expression of stemness‐related and cell‐cycle‐related genes in recurrent GBM cells. Further, we observed that recurrent GBM tissues showed a decreased proportion of microglia, consistent with previous reports, and that vascular endothelial growth factor A expression and the blood–brain barrier permeability were high, and the O6‐methylguanine DNA methyltransferase‐related signaling pathway was activated in recurrent GBM. Our results provide new insights into treatment strategies for recurrent glioblastomas.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.15773</identifier><identifier>PMID: 36853018</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Angiogenesis ; Blood-brain barrier ; Brain tumors ; cancer microenvironment ; Cancer therapies ; Cells ; Chemotherapy ; DNA methyltransferase ; Drug resistance ; Gene expression ; Glioblastoma ; Glioblastoma multiforme ; Growth factors ; Ligands ; Membrane permeability ; Methylguanine ; Microglia ; Original ; ORIGINAL ARTICLES ; Radiation therapy ; recurrent glioblastoma ; scRNA‐seq ; Signal transduction ; Software ; Survival analysis ; Transcriptomes ; tumor heterogeneity ; Tumor microenvironment ; Vascular endothelial growth factor</subject><ispartof>Cancer science, 2023-06, Vol.114 (6), p.2609-2621</ispartof><rights>2023 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2023. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4683-5d4bf92a519aeabfe26d9b8f10b888ff408c17a2386a22e116940d04b0e81b883</citedby><cites>FETCH-LOGICAL-c4683-5d4bf92a519aeabfe26d9b8f10b888ff408c17a2386a22e116940d04b0e81b883</cites><orcidid>0000-0001-9018-8067 ; 0000-0001-8628-4232</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10236634/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10236634/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1411,11543,27903,27904,45553,45554,46030,46454,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36853018$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Haibin</creatorcontrib><creatorcontrib>Guo, Chengcheng</creatorcontrib><creatorcontrib>Wang, Chaoye</creatorcontrib><creatorcontrib>Xu, Jiang</creatorcontrib><creatorcontrib>Zheng, Suyue</creatorcontrib><creatorcontrib>Duan, Jian</creatorcontrib><creatorcontrib>Li, Yiyun</creatorcontrib><creatorcontrib>Bai, Hongming</creatorcontrib><creatorcontrib>Xu, Qiuyan</creatorcontrib><creatorcontrib>Ning, Fangling</creatorcontrib><creatorcontrib>Wang, Feng</creatorcontrib><creatorcontrib>Yang, Qunying</creatorcontrib><title>Single‐cell RNA sequencing reveals tumor heterogeneity, microenvironment, and drug‐resistance mechanisms of recurrent glioblastoma</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>Glioblastomas are highly heterogeneous brain tumors. Despite the availability of standard treatment for glioblastoma multiforme (GBM), i.e., Stupp protocol, which involves surgical resection followed by radiotherapy and chemotherapy, glioblastoma remains refractory to treatment and recurrence is inevitable. Moreover, the biology of recurrent glioblastoma remains unclear. Increasing evidence has shown that intratumoral heterogeneity and the tumor microenvironment contribute to therapeutic resistance. However, the interaction between intracellular heterogeneity and drug resistance in recurrent GBMs remains controversial. The aim of this study was to map the transcriptome landscape of cancer cells and the tumor heterogeneity and tumor microenvironment in recurrent and drug‐resistant GBMs at a single‐cell resolution and further explore the mechanism of drug resistance of GBMs. We analyzed six tumor tissue samples from three patients with primary GBM and three patients with recurrent GBM in which recurrence and drug resistance developed after treatment with the standard Stupp protocol using single‐cell RNA sequencing. Using unbiased clustering, nine major cell clusters were identified. Upregulation of the expression of stemness‐related and cell‐cycle‐related genes was observed in recurrent GBM cells. Compared with the initial GBM tissues, recurrent GBM tissues showed a decreased proportion of microglia, consistent with previous reports. Finally, vascular endothelial growth factor A expression and the blood–brain barrier permeability were high, and the O6‐methylguanine DNA methyltransferase‐related signaling pathway was activated in recurrent GBM. Our results delineate the single‐cell map of recurrent glioblastoma, tumor heterogeneity, tumor microenvironment, and drug‐resistance mechanisms, providing new insights into treatment strategies for recurrent glioblastomas.
We observed upregulation of the expression of stemness‐related and cell‐cycle‐related genes in recurrent GBM cells. Further, we observed that recurrent GBM tissues showed a decreased proportion of microglia, consistent with previous reports, and that vascular endothelial growth factor A expression and the blood–brain barrier permeability were high, and the O6‐methylguanine DNA methyltransferase‐related signaling pathway was activated in recurrent GBM. Our results provide new insights into treatment strategies for recurrent glioblastomas.</description><subject>Angiogenesis</subject><subject>Blood-brain barrier</subject><subject>Brain tumors</subject><subject>cancer microenvironment</subject><subject>Cancer therapies</subject><subject>Cells</subject><subject>Chemotherapy</subject><subject>DNA methyltransferase</subject><subject>Drug resistance</subject><subject>Gene expression</subject><subject>Glioblastoma</subject><subject>Glioblastoma multiforme</subject><subject>Growth factors</subject><subject>Ligands</subject><subject>Membrane permeability</subject><subject>Methylguanine</subject><subject>Microglia</subject><subject>Original</subject><subject>ORIGINAL ARTICLES</subject><subject>Radiation therapy</subject><subject>recurrent glioblastoma</subject><subject>scRNA‐seq</subject><subject>Signal transduction</subject><subject>Software</subject><subject>Survival analysis</subject><subject>Transcriptomes</subject><subject>tumor heterogeneity</subject><subject>Tumor microenvironment</subject><subject>Vascular endothelial growth factor</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kU1rFTEUhgdRbK0u_AMScKPQafM1SWZVLhe_oChYXYdM5szclElSk5krd-fKtb_RX2LaW4sKZpOQPDzn5LxV9ZTgE1LWqTX5hDRSsnvVIWG8rSXG4v7NWdYtZvSgepTzJcZM8JY_rA6YUA3DRB1W3y9cGCf4-e2HhWlCH9-vUIYvCwRb7lGCLZgpo3nxMaENzJDiCAHcvDtG3tkUIWxdisFDmI-RCT3q0zIWW4Ls8myCBeTBbkxw2WcUh6K0S0oFR-PkYjeZPEdvHlcPhlIIntzuR9Xn168-rd_W5x_evFuvzmvLhWJ10_NuaKlpSGvAdANQ0bedGgjulFLDwLGyRBrKlDCUAiGi5bjHvMOgSEHYUXW2914tnYfelj6SmfRVct6knY7G6b9fgtvoMW41wZQJwXgxvLg1pFjmlGftXb6enQkQl6ypVFgKThtZ0Of_oJdxSaH8T1NFS2CNVKRQL_dUmWbOCYa7bgjW1_HqEq--ibewz_5s_478nWcBTvfAVzfB7v8mvV5d7JW_AGu8tHc</recordid><startdate>202306</startdate><enddate>202306</enddate><creator>Wu, Haibin</creator><creator>Guo, Chengcheng</creator><creator>Wang, Chaoye</creator><creator>Xu, Jiang</creator><creator>Zheng, Suyue</creator><creator>Duan, Jian</creator><creator>Li, Yiyun</creator><creator>Bai, Hongming</creator><creator>Xu, Qiuyan</creator><creator>Ning, Fangling</creator><creator>Wang, Feng</creator><creator>Yang, Qunying</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9018-8067</orcidid><orcidid>https://orcid.org/0000-0001-8628-4232</orcidid></search><sort><creationdate>202306</creationdate><title>Single‐cell RNA sequencing reveals tumor heterogeneity, microenvironment, and drug‐resistance mechanisms of recurrent glioblastoma</title><author>Wu, Haibin ; Guo, Chengcheng ; Wang, Chaoye ; Xu, Jiang ; Zheng, Suyue ; Duan, Jian ; Li, Yiyun ; Bai, Hongming ; Xu, Qiuyan ; Ning, Fangling ; Wang, Feng ; Yang, Qunying</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4683-5d4bf92a519aeabfe26d9b8f10b888ff408c17a2386a22e116940d04b0e81b883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Angiogenesis</topic><topic>Blood-brain barrier</topic><topic>Brain tumors</topic><topic>cancer microenvironment</topic><topic>Cancer therapies</topic><topic>Cells</topic><topic>Chemotherapy</topic><topic>DNA methyltransferase</topic><topic>Drug resistance</topic><topic>Gene expression</topic><topic>Glioblastoma</topic><topic>Glioblastoma multiforme</topic><topic>Growth factors</topic><topic>Ligands</topic><topic>Membrane permeability</topic><topic>Methylguanine</topic><topic>Microglia</topic><topic>Original</topic><topic>ORIGINAL ARTICLES</topic><topic>Radiation therapy</topic><topic>recurrent glioblastoma</topic><topic>scRNA‐seq</topic><topic>Signal transduction</topic><topic>Software</topic><topic>Survival analysis</topic><topic>Transcriptomes</topic><topic>tumor heterogeneity</topic><topic>Tumor microenvironment</topic><topic>Vascular endothelial growth factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Haibin</creatorcontrib><creatorcontrib>Guo, Chengcheng</creatorcontrib><creatorcontrib>Wang, Chaoye</creatorcontrib><creatorcontrib>Xu, Jiang</creatorcontrib><creatorcontrib>Zheng, Suyue</creatorcontrib><creatorcontrib>Duan, Jian</creatorcontrib><creatorcontrib>Li, Yiyun</creatorcontrib><creatorcontrib>Bai, Hongming</creatorcontrib><creatorcontrib>Xu, Qiuyan</creatorcontrib><creatorcontrib>Ning, Fangling</creatorcontrib><creatorcontrib>Wang, Feng</creatorcontrib><creatorcontrib>Yang, Qunying</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Haibin</au><au>Guo, Chengcheng</au><au>Wang, Chaoye</au><au>Xu, Jiang</au><au>Zheng, Suyue</au><au>Duan, Jian</au><au>Li, Yiyun</au><au>Bai, Hongming</au><au>Xu, Qiuyan</au><au>Ning, Fangling</au><au>Wang, Feng</au><au>Yang, Qunying</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Single‐cell RNA sequencing reveals tumor heterogeneity, microenvironment, and drug‐resistance mechanisms of recurrent glioblastoma</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2023-06</date><risdate>2023</risdate><volume>114</volume><issue>6</issue><spage>2609</spage><epage>2621</epage><pages>2609-2621</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>Glioblastomas are highly heterogeneous brain tumors. Despite the availability of standard treatment for glioblastoma multiforme (GBM), i.e., Stupp protocol, which involves surgical resection followed by radiotherapy and chemotherapy, glioblastoma remains refractory to treatment and recurrence is inevitable. Moreover, the biology of recurrent glioblastoma remains unclear. Increasing evidence has shown that intratumoral heterogeneity and the tumor microenvironment contribute to therapeutic resistance. However, the interaction between intracellular heterogeneity and drug resistance in recurrent GBMs remains controversial. The aim of this study was to map the transcriptome landscape of cancer cells and the tumor heterogeneity and tumor microenvironment in recurrent and drug‐resistant GBMs at a single‐cell resolution and further explore the mechanism of drug resistance of GBMs. We analyzed six tumor tissue samples from three patients with primary GBM and three patients with recurrent GBM in which recurrence and drug resistance developed after treatment with the standard Stupp protocol using single‐cell RNA sequencing. Using unbiased clustering, nine major cell clusters were identified. Upregulation of the expression of stemness‐related and cell‐cycle‐related genes was observed in recurrent GBM cells. Compared with the initial GBM tissues, recurrent GBM tissues showed a decreased proportion of microglia, consistent with previous reports. Finally, vascular endothelial growth factor A expression and the blood–brain barrier permeability were high, and the O6‐methylguanine DNA methyltransferase‐related signaling pathway was activated in recurrent GBM. Our results delineate the single‐cell map of recurrent glioblastoma, tumor heterogeneity, tumor microenvironment, and drug‐resistance mechanisms, providing new insights into treatment strategies for recurrent glioblastomas.
We observed upregulation of the expression of stemness‐related and cell‐cycle‐related genes in recurrent GBM cells. Further, we observed that recurrent GBM tissues showed a decreased proportion of microglia, consistent with previous reports, and that vascular endothelial growth factor A expression and the blood–brain barrier permeability were high, and the O6‐methylguanine DNA methyltransferase‐related signaling pathway was activated in recurrent GBM. Our results provide new insights into treatment strategies for recurrent glioblastomas.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>36853018</pmid><doi>10.1111/cas.15773</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-9018-8067</orcidid><orcidid>https://orcid.org/0000-0001-8628-4232</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Angiogenesis Blood-brain barrier Brain tumors cancer microenvironment Cancer therapies Cells Chemotherapy DNA methyltransferase Drug resistance Gene expression Glioblastoma Glioblastoma multiforme Growth factors Ligands Membrane permeability Methylguanine Microglia Original ORIGINAL ARTICLES Radiation therapy recurrent glioblastoma scRNA‐seq Signal transduction Software Survival analysis Transcriptomes tumor heterogeneity Tumor microenvironment Vascular endothelial growth factor |
title | Single‐cell RNA sequencing reveals tumor heterogeneity, microenvironment, and drug‐resistance mechanisms of recurrent glioblastoma |
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