Deciphering the complex role of thrombospondin-1 in glioblastoma development

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-Jacques Feige, Hrvoje Miletic, Marco Rossi, Lorenzo Bello, Francesco Falciani, Rolf Bjerkvig and Andréas Bikfalvi ()
Additional contact information
Thomas Daubon: Institut Nationale de la Santé et de la Recherche Médicale
Céline Léon: Institut Nationale de la Santé et de la Recherche Médicale
Kim Clarke: University of Liverpool
Laetitia Andrique: Institut Nationale de la Santé et de la Recherche Médicale
Laura Salabert: Institut Nationale de la Santé et de la Recherche Médicale
Elodie Darbo: University of Bordeaux
Raphael Pineau: University Bordeaux
Sylvaine Guérit: Institut Nationale de la Santé et de la Recherche Médicale
Marlène Maitre: Pathophysiology of Addiction Group
Stéphane Dedieu: MEDyC
Albin Jeanne: MEDyC
Sabine Bailly: INSERM U1036
Jean-Jacques Feige: INSERM U1036
Hrvoje Miletic: University of Bergen
Marco Rossi: Universita Degli Studi di Milano
Lorenzo Bello: Universita Degli Studi di Milano
Francesco Falciani: University of Liverpool
Rolf Bjerkvig: University of Bergen
Andréas Bikfalvi: Institut Nationale de la Santé et de la Recherche Médicale

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08480-y

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