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      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in glioma

      research-article
      Author(s): a , b , 1 , a , b , 1 , a , a , a , b , c , a , d , a , b , a , b , a , a , b , a , b , a , b , * , a , b , *
      Publication date (Electronic):
      Journal: EBioMedicine
      Publisher: Elsevier
      Keywords: DNA damage repair, Microglia, Glioma microenvironment, p53, Midkine, BER, base excision repair, CCL2, C-C motif chemokine ligand 2, CGGA, The Chinese Glioma Genome Atlas dataset, ChIP, Chromatin immunoprecipitation, CNV, copy number variation, DAB, Diaminobenzidine, DAPI, 4′,6-diamidino-2-phenylindole, DDR, DNA damage response, DMEM, Dulbecco's Modified Eagle Medium, DR, direct repair, DSBR, DNA double-strand break repair, ELISA, Enzyme-Linked Immunosorbent Assay, EM/PM classification, EGFR module / PDGFRA (platelet derived growth factor receptor A) -based molecular classification , FA, Fanconi anemia, FBS, fetal bovine serum, FC, fold change, GBM, glioblastoma, GCM, glioma-conditioned medium, GME, glioma microenvironment, GO, gene ontology, GSEA, gene set enrichment analysis, HR, homologous recombination, IF, immunofluorescence, IGV, Integrative Genomics Viewer, IHC, immunohistochemistry, KEGG, Kyoto Encyclopedia of Genes and Genomes, LGG, lower grade glioma, MDK, midkine, MEM, Minimum Essential Media, MGMT, O6-methylguanine-DNA methyltransferase, MMR, mismatch repair, NER, nucleotide excision repair, NFκB, nuclear factor kappa B, NHEJ, nonhomologous end joining, PBS, phosphate buffered saline, Pen/Strep, penicillin/streptomycin, PI, protease inhibitor, qRT-PCR, Quantitative real-time reverse transcription-polymerase chain reaction, SNP, single nucleotide polymorphism, SSBR, DNA single-strand break repair, ssGSEA, single sample gene set enrichment analysis, TBST, Tris-buffered Saline with Tween 20, TCGA, The Cancer Genome Atlas dataset, TLS, trans-lesion synthesis, TMZ, temozolomide, TNFA, tumor necrosis factor alpha, γH2AX, phosphorylated on serine 139 on H2A histone family member X, AKT, protein kinase B, ATM, ataxia telangiectasia-mutated gene, TP53, tumor protein P53, ATR, Ataxia Telangiectasia And Rad3-Related Protein, C5, Complement C5, IL6, interleukin 6, TNFSF4, TNF superfamily member 4, SAA1, serum amyloid A1, VEGFA, vascular endothelial growth factor A, HRP, horseradish peroxidase, Arg1, arginase 1, Fizz1, found in inflammatory zone 1, Mrc1, mannose receptor C-type 1, IDH, isocitrate dehydrogenase (NADP(+)), ATRX, alpha thalassemia/mental retardation syndrome X-linked, EGFR, epidermal growth factor receptor, PTEN, phosphatase and tensin homolog, NADP, nicotinamide adenine dinucleotide phosphate;, SWI/SNF, SWItch/Sucrose Non-Fermentable.

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          Abstract

          Background

          DNA damage repair (DDR) alterations are important events in cancer initiation, progression, and therapeutic resistance. However, the involvement of DDR alterations in glioma malignancy needs further investigation. This study aims to characterize the clinical and molecular features of gliomas with DDR alterations and elucidate the biological process of DDR alterations that regulate the cross talk between gliomas and the tumor microenvironment.

          Methods

          Integrated transcriptomic and genomic analyses were undertaken to conduct a comprehensive investigation of the role of DDR alterations in glioma. The prognostic DDR-related cytokines were identified from multiple datasets. In vivo and in vitro experiments validated the role of p53, the key molecule of DDR, regulating M2 polarization of microglia in glioma.

          Findings

          DDR alterations are associated with clinical and molecular characteristics of glioma. Gliomas with DDR alterations exhibit distinct immune phenotypes, and immune cell types and cytokine processes. DDR-related cytokines have an unfavorable prognostic implication for GBM patients and are synergistic with DDR alterations. Overexpression of MDK mediated by p53, the key transcriptional factor in DDR pathways, remodels the GBM immunosuppressive microenvironment by promoting M2 polarization of microglia, suggesting a potential role of DDR in regulating the glioma microenvironment.

          Interpretation

          Our work suggests that DDR alterations significantly contribute to remodeling the glioma microenvironment via regulating the immune response and cytokine pathways.

          Fund

          This study was supported by: 1. The National Key Research and Development Plan (No. 2016YFC0902500); 2. National Natural Science Foundation of China (No. 81702972, No. 81874204, No. 81572701, No. 81772666); 3. China Postdoctoral Science Foundation (2018M640305); 4. Special Fund Project of Translational Medicine in the Chinese-Russian Medical Research Center (No. CR201812); 5. The Research Project of the Chinese Society of Neuro-oncology, CACA (CSNO-2016-MSD12); 6. The Research Project of the Health and Family Planning Commission of Heilongjiang Province (2017–201); and 7. Harbin Medical University Innovation Fund (2017LCZX37, 2017RWZX03).

          Highlights

          • •

            Gliomas with DNA damage repair alterations had distinct genomic variation spectrum.

          • •

            DDR alterations exhibit distinct immune phenotypes, cytokine processes and immune cell types in glioma.

          • •

            DDR-related cytokines in GME have an unfavorable prognostic implication for GBM patients.

          • •

            P53-mediated midkine expression derived from glioma cells promotes M2 polarization of microglia.

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          Most cited references56

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          Microglia and macrophages in brain homeostasis and disease

          Qingyun Li, Ben A. Barres (2017)
          Microglia and non-parenchymal macrophages in the brain are mononuclear phagocytes that are increasingly recognized to be essential players in the development, homeostasis and diseases of the central nervous system. With the availability of new genetic, molecular and pharmacological tools, considerable advances have been made towards our understanding of the embryonic origins, developmental programmes and functions of these cells. These exciting discoveries, some of which are still controversial, also raise many new questions, which makes brain macrophage biology a fast-growing field at the intersection of neuroscience and immunology. Here, we review the current knowledge of how and where brain macrophages are generated, with a focus on parenchymal microglia. We also discuss their normal functions during development and homeostasis, the disturbance of which may lead to various neurodegenerative and neuropsychiatric diseases.
          Article 0 comments Cited 669 times – based on 0 reviews     Review now
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            Live or let die: the cell's response to p53.

            Karen H. Vousden, Xin Lu (2002)
            Article 0 comments Cited 617 times – based on 0 reviews     Review now
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              Immune regulation by helminth parasites: cellular and molecular mechanisms.

              Rick Maizels, Maria Yazdanbakhsh (2003)
              Immunology was founded by studying the body's response to infectious microorganisms, and yet microbial prokaryotes only tell half the story of the immune system. Eukaryotic pathogens--protozoa, helminths, fungi and ectoparasites--have all been powerful selective forces for immune evolution. Often, as with lethal protozoal parasites, the focus has been on acute infections and the inflammatory responses they evoke. Long-lived parasites such as the helminths, however, are more remarkable for their ability to downregulate host immunity, protecting themselves from elimination and minimizing severe pathology in the host.
              Article 0 comments Cited 333 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Chuanlu Jiang
                Jinquan Cai
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 14 February 2019
                Publication date Collection: March 2019
                Publication date (Electronic): 14 February 2019
                Volume: 41
                Pages: 185-199
                Affiliations
                [a ]Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
                [b ]Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
                [c ]Department of Laboratory Diagnosis, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
                [d ]Neurosurgical department, Bashkir State Medical University, Ufa 450008, Russia
                Author notes
                [* ]Corresponding authors at: Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin, China. jcl6688@ 123456163.com caijinquan666777@ 123456126.com
                [1]

                These authors have contributed equally to the work.

                Article
                Publisher ID: S2352-3964(19)30043-X
                DOI: 10.1016/j.ebiom.2019.01.067
                PMC ID: 6442002
                PubMed ID: 30773478
                SO-VID: 9daf3667-8eb6-4488-9d46-0599687c841e
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 29 September 2018
                Date revision received : 16 January 2019
                Date accepted : 17 January 2019
                Categories
                Subject: Research paper

                Keywords: dna damage repair,microglia,glioma microenvironment,p53,midkine,ber, base excision repair,ccl2, c-c motif chemokine ligand 2,cgga, the chinese glioma genome atlas dataset,chip, chromatin immunoprecipitation,cnv, copy number variation,dab, diaminobenzidine,dapi, 4′,6-diamidino-2-phenylindole,ddr, dna damage response,dmem, dulbecco's modified eagle medium,dr, direct repair,dsbr, dna double-strand break repair,elisa, enzyme-linked immunosorbent assay,em/pm classification, egfr module / pdgfra (platelet derived growth factor receptor a) -based molecular classification,fa, fanconi anemia,fbs, fetal bovine serum,fc, fold change,gbm, glioblastoma,gcm, glioma-conditioned medium,gme, glioma microenvironment,go, gene ontology,gsea, gene set enrichment analysis,hr, homologous recombination,if, immunofluorescence,igv, integrative genomics viewer,ihc, immunohistochemistry,kegg, kyoto encyclopedia of genes and genomes,lgg, lower grade glioma,mdk, midkine,mem, minimum essential media,mgmt, o6-methylguanine-dna methyltransferase,mmr, mismatch repair,ner, nucleotide excision repair,nfκb, nuclear factor kappa b,nhej, nonhomologous end joining,pbs, phosphate buffered saline,pen/strep, penicillin/streptomycin,pi, protease inhibitor,qrt-pcr, quantitative real-time reverse transcription-polymerase chain reaction,snp, single nucleotide polymorphism,ssbr, dna single-strand break repair,ssgsea, single sample gene set enrichment analysis,tbst, tris-buffered saline with tween 20,tcga, the cancer genome atlas dataset,tls, trans-lesion synthesis,tmz, temozolomide,tnfa, tumor necrosis factor alpha,γh2ax, phosphorylated on serine 139 on h2a histone family member x,akt, protein kinase b,atm, ataxia telangiectasia-mutated gene,tp53, tumor protein p53,atr, ataxia telangiectasia and rad3-related protein,c5, complement c5,il6, interleukin 6,tnfsf4, tnf superfamily member 4,saa1, serum amyloid a1,vegfa, vascular endothelial growth factor a,hrp, horseradish peroxidase,arg1, arginase 1,fizz1, found in inflammatory zone 1,mrc1, mannose receptor c-type 1,idh, isocitrate dehydrogenase (nadp(+)),atrx, alpha thalassemia/mental retardation syndrome x-linked,egfr, epidermal growth factor receptor,pten, phosphatase and tensin homolog,nadp, nicotinamide adenine dinucleotide phosphate;,swi/snf, switch/sucrose non-fermentable.
                Data availability:
                Keywords: dna damage repair, microglia, glioma microenvironment, p53, midkine, ber, base excision repair, ccl2, c-c motif chemokine ligand 2, cgga, the chinese glioma genome atlas dataset, chip, chromatin immunoprecipitation, cnv, copy number variation, dab, diaminobenzidine, dapi, 4′,6-diamidino-2-phenylindole, ddr, dna damage response, dmem, dulbecco's modified eagle medium, dr, direct repair, dsbr, dna double-strand break repair, elisa, enzyme-linked immunosorbent assay, em/pm classification, egfr module / pdgfra (platelet derived growth factor receptor a) -based molecular classification, fa, fanconi anemia, fbs, fetal bovine serum, fc, fold change, gbm, glioblastoma, gcm, glioma-conditioned medium, gme, glioma microenvironment, go, gene ontology, gsea, gene set enrichment analysis, hr, homologous recombination, if, immunofluorescence, igv, integrative genomics viewer, ihc, immunohistochemistry, kegg, kyoto encyclopedia of genes and genomes, lgg, lower grade glioma, mdk, midkine, mem, minimum essential media, mgmt, o6-methylguanine-dna methyltransferase, mmr, mismatch repair, ner, nucleotide excision repair, nfκb, nuclear factor kappa b, nhej, nonhomologous end joining, pbs, phosphate buffered saline, pen/strep, penicillin/streptomycin, pi, protease inhibitor, qrt-pcr, quantitative real-time reverse transcription-polymerase chain reaction, snp, single nucleotide polymorphism, ssbr, dna single-strand break repair, ssgsea, single sample gene set enrichment analysis, tbst, tris-buffered saline with tween 20, tcga, the cancer genome atlas dataset, tls, trans-lesion synthesis, tmz, temozolomide, tnfa, tumor necrosis factor alpha, γh2ax, phosphorylated on serine 139 on h2a histone family member x, akt, protein kinase b, atm, ataxia telangiectasia-mutated gene, tp53, tumor protein p53, atr, ataxia telangiectasia and rad3-related protein, c5, complement c5, il6, interleukin 6, tnfsf4, tnf superfamily member 4, saa1, serum amyloid a1, vegfa, vascular endothelial growth factor a, hrp, horseradish peroxidase, arg1, arginase 1, fizz1, found in inflammatory zone 1, mrc1, mannose receptor c-type 1, idh, isocitrate dehydrogenase (nadp(+)), atrx, alpha thalassemia/mental retardation syndrome x-linked, egfr, epidermal growth factor receptor, pten, phosphatase and tensin homolog, nadp, nicotinamide adenine dinucleotide phosphate;, swi/snf, switch/sucrose non-fermentable.

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