Glioblastoma cell populations with distinct oncogenic programs release podoplanin as procoagulant extracellular vesicles

  • Nadim Tawil
    Department of Experimental Medicine, McGill University, Montreal, QC, Canada;
  • Rayhaan Bassawon
    Research Institute of the McGill University Health Centre, Montreal, QC, Canada;
  • Brian Meehan
    Research Institute of the McGill University Health Centre, Montreal, QC, Canada;
  • Ali Nehme
    McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada;
  • Laura Montermini
    Research Institute of the McGill University Health Centre, Montreal, QC, Canada;
  • Tenzin Gayden
    Department of Human Genetics, McGill University, Montreal, QC, Canada;
  • Nicolas De Jay
    Department of Human Genetics, McGill University, Montreal, QC, Canada;
  • Cristiana Spinelli
    Research Institute of the McGill University Health Centre, Montreal, QC, Canada;
  • Shilpa Chennakrishnaiah
    Department of Experimental Medicine, McGill University, Montreal, QC, Canada;
  • Dongsic Choi
    Research Institute of the McGill University Health Centre, Montreal, QC, Canada;
  • Lata Adnani
    Research Institute of the McGill University Health Centre, Montreal, QC, Canada;
  • Michele Zeinieh
    Research Institute of the McGill University Health Centre, Montreal, QC, Canada;
  • Nada Jabado
    Research Institute of the McGill University Health Centre, Montreal, QC, Canada;
  • Claudia L. Kleinman
    Department of Human Genetics, McGill University, Montreal, QC, Canada;
  • Michael Witcher
    Department of Experimental Medicine, McGill University, Montreal, QC, Canada;
  • Yasser Riazalhosseini
    McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada;
  • Nigel S. Key
    Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC;
  • David Schiff
    Department of Neurology, University of Virginia, Charlottesville, VA;
  • Steven P. Grover
    Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC;
  • Nigel Mackman
    Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC;
  • Charles P. Couturier
    Montreal Neurological Institute, McGill University, Montreal, QC, Canada;
  • Kevin Petrecca
    Montreal Neurological Institute, McGill University, Montreal, QC, Canada;
  • Mario L. Suvà
    Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA;
  • Anoop Patel
    Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; and
  • Itay Tirosh
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
  • Hamed Najafabadi
    McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada;
  • Janusz Rak
    Department of Experimental Medicine, McGill University, Montreal, QC, Canada;

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<jats:title>Abstract</jats:title> <jats:p>Vascular anomalies, including local and peripheral thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of deregulation of the cancer cell genome and epigenome. Although the molecular effectors of these changes are poorly understood, the upregulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk for venous thromboembolism (VTE) in GBM patients. Therefore, regulation of this platelet-activating protein by transforming events in cancer cells is of considerable interest. We used single-cell and bulk transcriptome data mining, as well as cellular and xenograft models in mice, to analyze the nature of cells expressing PDPN, as well as their impact on the activation of the coagulation system and platelets. We report that PDPN is expressed by distinct (mesenchymal) GBM cell subpopulations and downregulated by oncogenic mutations of EGFR and IDH1 genes, along with changes in chromatin modifications (enhancer of zeste homolog 2) and DNA methylation. Glioma cells exteriorize their PDPN and/or tissue factor (TF) as cargo of exosome-like extracellular vesicles (EVs) shed from cells in vitro and in vivo. Injection of glioma-derived podoplanin carrying extracelluar vesicles (PDPN-EVs) activates platelets, whereas tissue factor carrying extracellular vesicles (TF-EVs) activate the clotting cascade. Similarly, an increase in platelet activation (platelet factor 4) or coagulation (D-dimer) markers occurs in mice harboring the corresponding glioma xenografts expressing PDPN or TF, respectively. Coexpression of PDPN and TF by GBM cells cooperatively affects tumor microthrombosis. Thus, in GBM, distinct cellular subsets drive multiple facets of cancer-associated thrombosis and may represent targets for phenotype- and cell type–based diagnosis and antithrombotic intervention.</jats:p>

収録刊行物

  • Blood Advances

    Blood Advances 5 (6), 1682-1694, 2021-03-15

    American Society of Hematology

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