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Deciphering the complex role of thrombospondin-1 in glioblastoma development

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  • Thomas Daubon

    (Institut Nationale de la Santé et de la Recherche Médicale
    University Bordeaux
    University of Bergen
    University of Bergen)

  • Céline Léon

    (Institut Nationale de la Santé et de la Recherche Médicale
    University Bordeaux)

  • Kim Clarke

    (University of Liverpool)

  • Laetitia Andrique

    (Institut Nationale de la Santé et de la Recherche Médicale
    University Bordeaux)

  • Laura Salabert

    (Institut Nationale de la Santé et de la Recherche Médicale
    University Bordeaux)

  • Elodie Darbo

    (University of Bordeaux)

  • Raphael Pineau

    (University Bordeaux)

  • Sylvaine Guérit

    (Institut Nationale de la Santé et de la Recherche Médicale
    University Bordeaux)

  • Marlène Maitre

    (Pathophysiology of Addiction Group)

  • Stéphane Dedieu

    (MEDyC)

  • Albin Jeanne

    (MEDyC
    SATT Nord)

  • Sabine Bailly

    (INSERM U1036)

  • Jean-Jacques Feige

    (INSERM U1036)

  • Hrvoje Miletic

    (University of Bergen
    Haukeland University Hospital)

  • Marco Rossi

    (Universita Degli Studi di Milano)

  • Lorenzo Bello

    (Universita Degli Studi di Milano)

  • Francesco Falciani

    (University of Liverpool)

  • Rolf Bjerkvig

    (University of Bergen
    University of Bergen
    Luxembourg Institute of Health)

  • Andréas Bikfalvi

    (Institut Nationale de la Santé et de la Recherche Médicale
    University Bordeaux)

Abstract

We undertook a systematic study focused on the matricellular protein Thrombospondin-1 (THBS1) to uncover molecular mechanisms underlying the role of THBS1 in glioblastoma (GBM) development. THBS1 was found to be increased with glioma grades. Mechanistically, we show that the TGFβ canonical pathway transcriptionally regulates THBS1, through SMAD3 binding to the THBS1 gene promoter. THBS1 silencing inhibits tumour cell invasion and growth, alone and in combination with anti-angiogenic therapy. Specific inhibition of the THBS1/CD47 interaction using an antagonist peptide decreases cell invasion. This is confirmed by CD47 knock-down experiments. RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas demonstrates that THBS1 is one of the gene with the highest connectivity at the tumour borders. All in all, these data show that TGFβ1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion. Furthermore, tumour cell-bound CD47 is implicated in this process.

Suggested Citation

  • Thomas Daubon & Céline Léon & Kim Clarke & Laetitia Andrique & Laura Salabert & Elodie Darbo & Raphael Pineau & Sylvaine Guérit & Marlène Maitre & Stéphane Dedieu & Albin Jeanne & Sabine Bailly & Jean, 2019. "Deciphering the complex role of thrombospondin-1 in glioblastoma development," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08480-y
    DOI: 10.1038/s41467-019-08480-y
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    Cited by:

    1. Feng Zhi & Bowen Li & Chuanxia Zhang & Fan Xia & Rong Wang & Weihong Xie & Sihui Cai & Dawei Zhang & Ren Kong & Yiqiao Hu & Yilin Yang & Ya Peng & Jun Cui, 2023. "NLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Yulia Dembitskaya & Andrew K. J. Boyce & Agata Idziak & Atefeh Pourkhalili Langeroudi & Misa Arizono & Jordan Girard & Guillaume Bourdellès & Mathieu Ducros & Marie Sato-Fitoussi & Amaia Ochoa de Amez, 2023. "Shadow imaging for panoptical visualization of brain tissue in vivo," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Mayuki Omatsu & Yuki Nakanishi & Kosuke Iwane & Naoki Aoyama & Angeles Duran & Yu Muta & Anxo Martinez-Ordoñez & Qixiu Han & Nobukazu Agatsuma & Kenta Mizukoshi & Munenori Kawai & Go Yamakawa & Mio Na, 2023. "THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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