STAT3 is essential for the maintenance of neurosphere-initiating tumor cells in patients with glioblastomas: A potential for targeted therapy?

Authors

  • Claire Villalva,

    1. INSERM U935, Université de Poitiers, Poitiers F-86021, France
    2. CHU de Poitiers, Laboratoire d'Hématologie et d'Oncologie Biologiques, Poitiers F-86021, France
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  • Severine Martin-Lannerée,

    1. Institut Cochin, Université René Descartes, CNRS (UMR8104), Paris, France
    2. INSERM U567, Paris, France
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  • Ulrich Cortes,

    1. INSERM U935, Université de Poitiers, Poitiers F-86021, France
    2. CHU de Poitiers, Laboratoire d'Hématologie et d'Oncologie Biologiques, Poitiers F-86021, France
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  • Fatima Dkhissi,

    1. INSERM U935, Université de Poitiers, Poitiers F-86021, France
    2. UMR7216 Epigénétique et Destin Cellulaire, CNRS, Université Paris-Diderot/Paris 7, 75013 Paris, France
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  • Michel Wager,

    1. Université de Poitiers, CHU de Poitiers, Service de Neurochirurgie, Poitiers F-86021, France
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  • Amélie Le Corf,

    1. INSERM U935, Université de Poitiers, Poitiers F-86021, France
    2. CHU de Poitiers, Laboratoire d'Hématologie et d'Oncologie Biologiques, Poitiers F-86021, France
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  • Jean-Marc Tourani,

    1. Université de Poitiers, CHU de Poitiers, Service d'Oncologie Médicale, Poitiers F-86021, France
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  • Isabelle Dusanter-Fourt,

    1. Institut Cochin, Université René Descartes, CNRS (UMR8104), Paris, France
    2. INSERM U567, Paris, France
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  • Ali G. Turhan,

    1. INSERM U935, Université de Poitiers, Poitiers F-86021, France
    2. CHU de Poitiers, Laboratoire d'Hématologie et d'Oncologie Biologiques, Poitiers F-86021, France
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  • Lucie Karayan-Tapon

    Corresponding author
    1. INSERM U935, Université de Poitiers, Poitiers F-86021, France
    2. CHU de Poitiers, Laboratoire d'Hématologie et d'Oncologie Biologiques, Poitiers F-86021, France
    3. Université de Poitiers, CHU de Poitiers, Service d'Oncologie Médicale, Poitiers F-86021, France
    • CHU de Poitiers, Laboratoire d'Hématologie et d'Oncologie Biologiques, Poitiers F-86021, France
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    • Tel.: +33549444988


Abstract

Glioblastoma (GBM), the highest-grade form of gliomas, is the most frequent and the most aggressive. Recently, a subpopulation of cells with stem cells characteristics, commonly named “tumor-initiating stem cells” (TISCs) or “cancer stem cells” (CSCs) were identified in GBM. These cells were shown to be highly resistant to chemotherapeutic drugs and to ionizing radiations. Consequently, the knowledge of the signals that regulate the functions and survival of TISCs is crucial. In our work, we describe a neurosphere-initiating cell (NS-IC) assay to quantify TISC/CSCs from patients with GBM and show that these cells are tumorigenic in vivo. We demonstrate that the intracellular signal transducer and activator of transcription STAT3 is constitutively activated by phosphorylation preferentially on serine 727 in these cells. Moreover, we demonstrate that the selective inhibition of STAT3 by the chemical compound Stattic or by siRNA STAT3 abrogates TISC/CSC proliferation and NS-IC suggesting that self-renewal of GBM “stem-like” cells depends on the presence of STAT3 for their maintenance. Finally, we show that inhibition of STAT3 by Stattic sensitizes TISC/CSCs to the inhibitory action of Temozolomide with a strong synergistic effect of both drugs. Overall, these results suggest that strategies focused on STAT3 inhibition are efficient at the level of “stem-like” cells and could be of interest for therapeutic purposes in patients with malignant GBM.

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