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The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers

Acta Neuropathologica volume 144, pages 1127–1142 (2022)Cite this article

Abstract

Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM–rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2–5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis.

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Acknowledgements

This work was partially supported by a CIHR Project Grant (PJT154357) to TK, the NIH/NCI under awards P30CA016042, U24CA248265 and P50CA211015 to PCB and TFRI 1065. This research was funded in part by the Ontario Ministry of Health and Long-Term Care. SKS and TK were supported through the Canadian Research Chair program. We thank Dr. Kaiyun Yang for her contribution in generating patient’s information.

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Author notes

  1. Nazanin Tatari, Shahbaz Khan and Julie Livingstone contributed equally to this work.

Authors and Affiliations

  1. Centre for Discovery in Cancer Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada

    Nazanin Tatari, Chirayu Chokshi, William D. Gwynne, Manoj Singh & Sheila K. Singh

  2. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Shahbaz Khan, Vladimir Ignatchenko & Thomas Kislinger

  3. Department of Human Genetics and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA

    Julie Livingstone, Chenghao Zhu & Paul C. Boutros

  4. Department of Surgery, McMaster University, Hamilton, ON, Canada

    Kui Zhai, Dillon Mckenna, Manoj Singh, Chitra Venugopal & Sheila K. Singh

  5. McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada

    Spencer Revill & Kjetil Ask

  6. Department of Molecular Genetics - Donnelly Centre, University of Toronto, Toronto, ON, Canada

    Nicholas Mikolajewicz, Hong Han & Jason Moffat

  7. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada

    Jennifer Chan

  8. Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Canada

    Cynthia Hawkins

  9. Department of Pathology, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada

    Jian-Qiang Lu & John P. Provias

  10. Department of Biochemistry and Molecular Biology, The University of Calgary, Calgary, AB, Canada

    Sorana Morrissy & Samuel Brown

  11. Department of Neurology and Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland

    Tobias Weiss & Michael Weller

  12. Juravinski Cancer Center, Department of Oncology, Radiation Oncology, McMaster University, Hamilton, ON, Canada

    Jeffrey N. Greenspoon

  13. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Paul C. Boutros & Thomas Kislinger

Authors
  1. Nazanin Tatari
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  2. Shahbaz Khan
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  3. Julie Livingstone
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Contributions

NT, SK, JL, CV, PCB, SKS and TK conceived of the study idea. NT, SK, JL, KZ, DM, VI, CC, WDG, MS, CZ, JC, CH, JQL, JPP, PKA, TW, MW, JNG, performed experiments and data analysis. NT, SK, JL, KZ, PCB, SKS and TK wrote the manuscript with input from all other authors. CV, PCB, SKS and TK supervised the study. All authors interpreted the data, reviewed the manuscript and approved the final version.

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Correspondence to Paul C. Boutros, Sheila K. Singh or Thomas Kislinger.

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Tatari, N., Khan, S., Livingstone, J. et al. The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers. Acta Neuropathol 144, 1127–1142 (2022). https://doi.org/10.1007/s00401-022-02506-4

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