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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Veröffentlicht in:Cancer science 2023-06, Vol.114 (6), p.2609-2621
Hauptverfasser: Wu, Haibin, Guo, Chengcheng, Wang, Chaoye, Xu, Jiang, Zheng, Suyue, Duan, Jian, Li, Yiyun, Bai, Hongming, Xu, Qiuyan, Ning, Fangling, Wang, Feng, Yang, Qunying
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container_issue 6
container_start_page 2609
container_title Cancer science
container_volume 114
creator Wu, Haibin
Guo, Chengcheng
Wang, Chaoye
Xu, Jiang
Zheng, Suyue
Duan, Jian
Li, Yiyun
Bai, Hongming
Xu, Qiuyan
Ning, Fangling
Wang, Feng
Yang, Qunying
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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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><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 &amp; 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 &amp; Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2023 The Authors. Cancer Science published by John Wiley &amp; 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. 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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. 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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. 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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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