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Cited by 437Glioma Diagnosis and TreatmentNeuroinflammation and Neurodegeneration MechanismsImmune cells in cancer

Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma

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Henrik Heiland, Dieter, Ravi, Vidhya M., Behringer, Simon P., Frenking, Jan Hendrik, Wurm, Julian, Joseph, Kevin, Garrelfs, Nicklas W. C., Strähle, Jakob +13 more·2019·Nature Communications
DOI 10.1038/s41467-019-10493-6PMC PMC6559986
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Abstract

Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. In malignant brain tumors, their function and crosstalk to other components of the environment is poorly understood. Here we report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. Subsequently, we investigate the origin of astrocytic transformation by a microglia loss-of-function model in a human organotypic slice model with injected tumor cells. RNA-seq based gene expression analysis of astrocytes reveals a distinct astrocytic phenotype caused by the coexistence of microglia and astrocytes in the tumor environment, which leads to a large release of anti-inflammatory cytokines such as TGFβ, IL10 and G-CSF. Inhibition of the JAK/STAT pathway shifts the balance of pro- and anti-inflammatory cytokines towards a pro-inflammatory environment. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses.

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  • Advanced statistics using multidimensional data and co-clustering approaches reveals that the A1 and A2 transcriptomes represent only two of many potential astrocyte transcriptomes segregating along several latent variables.

    “In addition, advanced statistics using multidimensional data and co-clustering approaches reveals that the A1 and A2 transcriptomes represent only two of many potential astrocyte transcriptomes segregating along several latent variables79.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [79]

    The Results section (page unavailable) describes a multidimensional analysis of astrocyte expression along maturation and inflammatory–alternative activation axes. The Discussion says the A2 phenotype may hide multiple reactive stages. The copy does not establish that A1 and A2 are just two of many astrocyte transcriptomes segregating along several latent variables, or describe a co-clustering approach to that conclusion. (LLM, conf=0.84)

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References 54 · Cited by 437

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  1. [1]Crocetti E Epidemiology of glial and non-glial brain tumours in Europe Eur. J. Cancer 2012 48 1532 1542 10.1016/j.ejca.2011.12.013 22227039 · DOI
  2. [2]Ostrom QT The epidemiology of glioma in adults: a “state of the science” review Neuro. Oncol. 2014 16 896 913 10.1093/neuonc/nou087 24842956 PMC4057143 · DOI
  3. [3]Ostrom QT CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011 Neuro. Oncol. 2014 16 Suppl 4 iv1 iv63 10.1093/neuonc/nou223 25304271 PMC4193675 · DOI
  4. [4]Gilbert MR A randomized trial of bevacizumab for newly diagnosed glioblastoma N. Engl. J. Med. 2014 370 699 708 10.1056/NEJMoa1308573 24552317 PMC4201043 · DOI · Paper page
  5. [5]Chinot OL Wick W Cloughesy T Bevacizumab for newly diagnosed glioblastoma N. Engl. J. Med. 2014 370 2049 10.1056/NEJMoa1308345 24860870 · DOI
  6. [6]Taal W Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial Lancet Oncol. 2014 15 943 953 10.1016/S1470-2045(14)70314-6 25035291 · DOI
  7. [7]Vredenburgh JJ Bevacizumab plus irinotecan in recurrent glioblastoma multiforme J. Clin. Oncol. 2007 25 4722 4729 10.1200/JCO.2007.12.2440 17947719 · DOI
  8. [8]Friedman HS Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma J. Clin. Oncol. 2009 27 4733 4740 10.1200/JCO.2008.19.8721 19720927 · DOI
  9. [9]Van Meir EG Exciting new advances in neuro-oncology CA Cancer J. Clin. 2010 60 166 193 10.3322/caac.20069 20445000 PMC2888474 · DOI · Paper page
  10. [10]Whiteside T L The tumor microenvironment and its role in promoting tumor growth Oncogene 2008 27 45 5904 5912 10.1038/onc.2008.271 18836471 PMC3689267 · DOI · Paper page
  11. [11]Darmanis S Single-cell RNA-Seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma Cell Rep. 2017 21 1399 1410 10.1016/j.celrep.2017.10.030 29091775 PMC5810554 · DOI
  12. [13]Zhang Y Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse Neuron 2016 89 37 53 10.1016/j.neuron.2015.11.013 26687838 PMC4707064 · DOI · Paper page
  13. [14]Matyash V Kettenmann H Heterogeneity in astrocyte morphology and physiology Brain Res. Rev. 2010 63 2 10 10.1016/j.brainresrev.2009.12.001 20005253 · DOI
  14. [15]Liddelow SA Barres BA Reactive astrocytes: production, function, and therapeutic potential Immunity 2017 46 957 967 10.1016/j.immuni.2017.06.006 28636962 · DOI · Paper page
  15. [17]Zamanian JL Genomic analysis of reactive astrogliosis J. Neurosci. 2012 32 6391 6410 10.1523/JNEUROSCI.6221-11.2012 22553043 PMC3480225 · DOI · Paper page
  16. [18]Priego Neibla Zhu Lucía Monteiro Cátia Mulders Manon Wasilewski David Bindeman Wendy Doglio Laura Martínez Liliana Martínez-Saez Elena Ramón y Cajal Santiago Megías Diego Hernández-Encinas Elena Blanco-Aparicio Carmen Martínez Lola Zarzuela Eduardo Muñoz Javier Fustero-Torre Coral Piñeiro-Yáñez Elena Hernández-Laín Aurelio Bertero Luca Poli Valeria Sanchez-Martinez Melchor Menendez Javier A. Soffietti Riccardo Bosch-Barrera Joaquim Valiente Manuel STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis Nature Medicine 2018 24 7 1024 1035 10.1038/s41591-018-0044-4 29892069 · DOI · Paper page
  17. [19]Yun Seung Pil Kam Tae-In Panicker Nikhil Kim SangMin Oh Yumin Park Jong-Sung Kwon Seung-Hwan Park Yong Joo Karuppagounder Senthilkumar S. Park Hyejin Kim Sangjune Oh Nayeon Kim Nayoung Alice Lee Saebom Brahmachari Saurav Mao Xiaobo Lee Jun Hee Kumar Manoj An Daniel Kang Sung-Ung Lee Yunjong Lee Kang Choon Na Dong Hee Kim Donghoon Lee Sang Hun Roschke Viktor V. Liddelow Shane A. Mari Zoltan Barres Ben A. Dawson Valina L. Lee Seulki Dawson Ted M. Ko Han Seok Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease Nature Medicine 2018 24 7 931 938 10.1038/s41591-018-0051-5 PMC6039259 29892066 · DOI · Paper page
  18. [20]Zschaler, J., Schlorke, D. & Arnhold, J. Differences in innate immune response between man and mouse. Crit. Rev. Immunol. (2014). 10.1615/critrevimmunol.2014011600 25404048 · DOI
  19. [21]Martinez F. O. Gordon S. Locati M. Mantovani A. Transcriptional Profiling of the Human Monocyte-to-Macrophage Differentiation and Polarization: New Molecules and Patterns of Gene Expression The Journal of Immunology 2006 177 10 7303 7311 10.4049/jimmunol.177.10.7303 17082649 · DOI
  20. [22]Hellwig, S. et al. Forebrain microglia from wild-type but not adult 5xFAD mice prevent amyloid-β plaque formation in organotypic hippocampal slice cultures. Sci. Rep. (2015). 10.1038/srep14624 PMC4586757 26416689 · DOI · Paper page
  21. [23]Keskin Derin B. Anandappa Annabelle J. Sun Jing Tirosh Itay Mathewson Nathan D. Li Shuqiang Oliveira Giacomo Giobbie-Hurder Anita Felt Kristen Gjini Evisa Shukla Sachet A. Hu Zhuting Li Letitia Le Phuong M. Allesøe Rosa L. Richman Alyssa R. Kowalczyk Monika S. Abdelrahman Sara Geduldig Jack E. Charbonneau Sarah Pelton Kristine Iorgulescu J. Bryan Elagina Liudmila Zhang Wandi Olive Oriol McCluskey Christine Olsen Lars R. Stevens Jonathan Lane William J. Salazar Andres M. Daley Heather Wen Patrick Y. Chiocca E. Antonio Harden Maegan Lennon Niall J. Gabriel Stacey Getz Gad Lander Eric S. Regev Aviv Ritz Jerome Neuberg Donna Rodig Scott J. Ligon Keith L. Suvà Mario L. Wucherpfennig Kai W. Hacohen Nir Fritsch Edward F. Livak Kenneth J. Ott Patrick A. Wu Catherine J. Reardon David A. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial Nature 2018 565 7738 234 239 10.1038/s41586-018-0792-9 30568305 PMC6546179 · DOI · Paper page
  22. [25]Li W Graeber MB The molecular profile of microglia under the influence of glioma Neuro. Oncol. 2012 14 958 978 10.1093/neuonc/nos116 22573310 PMC3408253 · DOI
  23. [26]Szulzewsky F Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1 PLoS One 2015 10 1 27 10.1371/journal.pone.0116644 PMC4320099 25658639 · DOI
  24. [27]Platten Michael T cells engineered to home in on brain cancer Nature 2018 561 7723 319 320 10.1038/d41586-018-05883-7 30224728 · DOI
  25. [31]He F A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis Nat. Neurosci. 2005 8 616 625 10.1038/nn1440 15852015 PMC4222251 · DOI
  26. [33]Ding X Silencing IFN-γ binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity J. Immunol. 2015 194 4251 4264 10.4049/jimmunol.1303321 25795755 PMC4402255 · DOI
  27. [35]Pittet CL Newcombe J Antel JP Arbour N The majority of infiltrating CD8 T lymphocytes in multiple sclerosis lesions is insensitive to enhanced PD-L1 levels on CNS cells Glia 2011 59 841 856 10.1002/glia.21158 21360758 PMC7165507 · DOI
  28. [36]Nduom EK Weller M Heimberger AB Immunosuppressive mechanisms in glioblastoma Neuro. Oncol. 2015 17 vii9 vii14 10.1093/neuonc/nov151 26516226 PMC4625890 · DOI
  29. [37]Platten, M., Ochs, K., Lemke, D., Opitz, C. & Wick, W. Microenvironmental clues for glioma immunotherapy. Curr. Neurol. Neurosci. Rep. 14, 440 (2014). 24604058
  30. [38]Li P Gallo V Huntsman M Mangin J-M Raymond M Chronic perinatal hypoxia reduces glutamate-aspartate transporter function in astrocytes through the janus kinase/signal transducer and activator of transcription pathway J. Neurosci. 2011 31 17864 17871 10.1523/JNEUROSCI.3179-11.2011 22159101 PMC3278804 · DOI
  31. [39]Rajappa P Malignant astrocytic tumor progression potentiated by JAK-mediated recruitment of myeloid cells Clin. Cancer Res. 2017 23 3109 3119 10.1158/1078-0432.CCR-16-1508 28039266 PMC5769921 · DOI
  32. [40]Heiland Dieter Henrik Gaebelein Annette Börries Melanie Wörner Jakob Pompe Nils Franco Pamela Heynckes Sabrina Bartholomae Mark hAilín Darren Ó. Carro Maria Stella Prinz Marco Weber Stefan Mader Irina Delev Daniel Schnell Oliver Microenvironment-Derived Regulation of HIF Signaling Drives Transcriptional Heterogeneity in Glioblastoma Multiforme Molecular Cancer Research 2018 16 4 655 668 10.1158/1541-7786.MCR-17-0680 29330292 · DOI
  33. [41]Watanabe M Antibody array analysis of peripheral and blood cytokine levels in rats after masseter inflammation Neurosci. Lett. 2005 382 128 133 10.1016/j.neulet.2005.03.002 15911135 · DOI
  34. [44]Wilkerson MD Hayes DN ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking Bioinformatics 2010 26 1572 1573 10.1093/bioinformatics/btq170 20427518 PMC2881355 · DOI
  35. [46]McCullagh P. Nelder J. A. Generalized Linear Models 1989 Boston, MA Springer US
  36. [48]Liberzon A Molecular signatures database (MSigDB) 3.0 Bioinformatics 2011 27 1739 1740 10.1093/bioinformatics/btr260 21546393 PMC3106198 · DOI · Paper page
  37. [50]Hahne, F. et al. flowCore: a Bioconductor package for high throughput flow cytometry. BMC Bioinform. (2009) 10.1186/1471-2105-10-106. PMC2684747 19358741 · DOI

Authors
Henrik Heiland, D., Ravi, V. M., Behringer, S. P., Frenking, J. H., Wurm, J., Joseph, K., Garrelfs, N. W. C., Strähle, J., Heynckes, S., Grauvogel, J., Franco, P., Mader, I., Schneider, M., Potthoff, A.-L., Delev, D., Hofmann, U. G., Fung, C., Beck, J., Sankowski, R., Prinz, M., & Schnell, O.
Affiliations
  • University of Freiburg (DE)
  • University of Bonn (DE)
  • RWTH Aachen University (DE)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-06-11
Volume
10
Issue
1
Pages
2541-2541
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-019-10493-6
PMC
PMC6559986
OpenAlex
W2949944282
Cited by
437
References
54
Citations by year
2026: 54 · 2025: 80 · 2024: 66 · 2023: 67 · 2022: 65 · 2021: 58 · 2020: 38 · 2019: 9
FWCI
23.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
German Cancer Society (Seeding Grand TII), Müller-Fahnenberg Stiftung Familie Mehdorn Stiftung
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
glioblastoma, JAK/STAT signaling, microglia, astrocyte-microglia interaction, immunosuppressive tumor microenvironment, anti-inflammatory cytokines, TGF-beta, IL-10, granulocyte colony-stimulating factor
MeSH terms
Astrocytes, Brain Neoplasms, Glioblastoma, Humans, Phenotype, Signal Transduction, Cytokines, Sequence Analysis, RNA, Microglia, Inflammation Mediators, Gene Expression Profiling, Cell Line, Tumor, Tissue Culture Techniques, STAT Transcription Factors, Janus Kinases

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