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Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma

Author

Listed:
  • Shannon Coy

    (Harvard Medical School
    Harvard Program in Therapeutic Science
    Harvard Medical School)

  • Shu Wang

    (Harvard Program in Therapeutic Science
    Harvard Medical School
    Harvard University)

  • Sylwia A. Stopka

    (Harvard Medical School)

  • Jia-Ren Lin

    (Harvard Program in Therapeutic Science
    Harvard Medical School)

  • Clarence Yapp

    (Harvard Program in Therapeutic Science
    Harvard Medical School)

  • Cecily C. Ritch

    (Harvard Medical School
    Harvard Program in Therapeutic Science)

  • Lisa Salhi

    (and AP-HP Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix)

  • Gregory J. Baker

    (Harvard Program in Therapeutic Science
    Harvard Medical School)

  • Rumana Rashid

    (Harvard Medical School
    Harvard Program in Therapeutic Science
    University of Pittsburgh-Carnegie Mellon)

  • Gerard Baquer

    (Harvard Medical School)

  • Michael Regan

    (Harvard Medical School)

  • Prasidda Khadka

    (Dana-Farber Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard)

  • Kristina A. Cole

    (University of Pennsylvania)

  • Jaeho Hwang

    (Harvard Medical School)

  • Patrick Y. Wen

    (Brigham and Women’s Hospital, Harvard Medical School
    Dana-Farber Cancer Institute)

  • Pratiti Bandopadhayay

    (Dana-Farber Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard)

  • Mariarita Santi

    (Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia
    University of Pennsylvania Perelman School of Medicine)

  • Thomas Raedt

    (University of Pennsylvania)

  • Keith L. Ligon

    (Harvard Medical School
    Dana-Farber Boston Children’s Cancer and Blood Disorders Center
    Dana-Farber Cancer Institute
    Boston Children’s Hospital)

  • Nathalie Y. R. Agar

    (Harvard Medical School)

  • Peter K. Sorger

    (Harvard Program in Therapeutic Science
    Harvard Medical School)

  • Mehdi Touat

    (and AP-HP Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix
    Brigham and Women’s Hospital, Harvard Medical School)

  • Sandro Santagata

    (Harvard Medical School
    Harvard Program in Therapeutic Science
    Harvard Medical School)

Abstract

How the glioma immune microenvironment fosters tumorigenesis remains incompletely defined. Here, we use single-cell RNA-sequencing and multiplexed tissue-imaging to characterize the composition, spatial organization, and clinical significance of extracellular purinergic signaling in glioma. We show that microglia are the predominant source of CD39, while tumor cells principally express CD73. In glioblastoma, CD73 is associated with EGFR amplification, astrocyte-like differentiation, and increased adenosine, and is linked to hypoxia. Glioblastomas enriched for CD73 exhibit inflammatory microenvironments, suggesting that purinergic signaling regulates immune adaptation. Spatially-resolved single-cell analyses demonstrate a strong spatial correlation between tumor-CD73 and microglial-CD39, with proximity associated with poor outcomes. Similar spatial organization is present in pediatric high-grade gliomas including H3K27M-mutant diffuse midline glioma. These data reveal that purinergic signaling in gliomas is shaped by genotype, lineage, and functional state, and that core enzymes expressed by tumor and myeloid cells are organized to promote adenosine-rich microenvironments potentially amenable to therapeutic targeting.

Suggested Citation

  • Shannon Coy & Shu Wang & Sylwia A. Stopka & Jia-Ren Lin & Clarence Yapp & Cecily C. Ritch & Lisa Salhi & Gregory J. Baker & Rumana Rashid & Gerard Baquer & Michael Regan & Prasidda Khadka & Kristina A, 2022. "Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32430-w
    DOI: 10.1038/s41467-022-32430-w
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    References listed on IDEAS

    as
    1. Dvir Aran & Marina Sirota & Atul J. Butte, 2015. "Systematic pan-cancer analysis of tumour purity," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    2. Matthias Gromeier & Michael C. Brown & Gao Zhang & Xiang Lin & Yeqing Chen & Zhi Wei & Nike Beaubier & Hai Yan & Yiping He & Annick Desjardins & James E. Herndon & Frederick S. Varn & Roel G. Verhaak , 2021. "Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
    3. Mehdi Touat & Yvonne Y. Li & Adam N. Boynton & Liam F. Spurr & J. Bryan Iorgulescu & Craig L. Bohrson & Isidro Cortes-Ciriano & Cristina Birzu & Jack E. Geduldig & Kristine Pelton & Mary Jane Lim-Fat , 2020. "Mechanisms and therapeutic implications of hypermutation in gliomas," Nature, Nature, vol. 580(7804), pages 517-523, April.
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    Cited by:

    1. Yuanning Zheng & Francisco Carrillo-Perez & Marija Pizurica & Dieter Henrik Heiland & Olivier Gevaert, 2023. "Spatial cellular architecture predicts prognosis in glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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