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; Andréas Bikfalvi

doi:10.1038/s41467-019-08480-y

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, Andréas Bikfalvi

^*Corresponding author for this work

Department of Cancer Research

Research output: Contribution to journal › Article › Research › peer-review

84 Citations (Scopus)

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.

Original language	English
Article number	1146
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-08480-y
Publication status	Published - 1 Dec 2019

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Daubon, T., Léon, C., Clarke, K., Andrique, L., Salabert, L., Darbo, E., Pineau, R., Guérit, S., Maitre, M., Dedieu, S., Jeanne, A., Bailly, S., Feige, J. J., Miletic, H., Rossi, M., Bello, L., Falciani, F., Bjerkvig, R., & Bikfalvi, A. (2019). Deciphering the complex role of thrombospondin-1 in glioblastoma development. Nature Communications, 10(1), [1146]. https://doi.org/10.1038/s41467-019-08480-y

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title = "Deciphering the complex role of thrombospondin-1 in glioblastoma development",

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.",

author = "Thomas Daubon and C{\'e}line L{\'e}on and Kim Clarke and Laetitia Andrique and Laura Salabert and Elodie Darbo and Raphael Pineau and Sylvaine Gu{\'e}rit and Marl{\`e}ne Maitre and St{\'e}phane Dedieu and Albin Jeanne and Sabine Bailly and Feige, {Jean Jacques} and Hrvoje Miletic and Marco Rossi and Lorenzo Bello and Francesco Falciani and Rolf Bjerkvig and Andr{\'e}as Bikfalvi",

note = "Funding Information: This work was supported by grants from INSERM (recurrent funding), and from the “Ligue contre le Cancer” to A.B. and by Helse Vest, Haukeland Hospital, The Norwegian Research Council and Stiftelsen Kristian Gerhard Jebsen Research Foundation for R.B. T.D. was a recipient of Norwegian Cancer Society. LCM facility is supported by LabEX BRAIN ANR-10-LABX-43 and FRM DGE20061007758. We thank A. Barre for first bioinformatics analysis of RNA-sequencing results. Library generation and sequencing were performed by L. Rainbow, C. Nelson and A. Lucaci, and the bioinformatics work was performed by R. Gregory at The Centre for Genomic Research, University of Liverpool and P. Koldkjaer for performing RNA-sequencing. We also thank M. Delugin, J. Massiere, M. Poulet and T. Chouleur for preliminary experiment, the Bordeaux Imaging Center for Nanozoomer use, M.P. Algeo, M.A. Derieppe, M. Campistron for animal treatments and care. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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doi = "10.1038/s41467-019-08480-y",

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Daubon, T, Léon, C, Clarke, K, Andrique, L, Salabert, L, Darbo, E, Pineau, R, Guérit, S, Maitre, M, Dedieu, S, Jeanne, A, Bailly, S, Feige, JJ, Miletic, H, Rossi, M, Bello, L, Falciani, F, Bjerkvig, R & Bikfalvi, A 2019, 'Deciphering the complex role of thrombospondin-1 in glioblastoma development', Nature Communications, vol. 10, no. 1, 1146. https://doi.org/10.1038/s41467-019-08480-y

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T1 - Deciphering the complex role of thrombospondin-1 in glioblastoma development

AU - Daubon, Thomas

AU - Léon, Céline

AU - Clarke, Kim

AU - Andrique, Laetitia

AU - Salabert, Laura

AU - Darbo, Elodie

AU - Pineau, Raphael

AU - Guérit, Sylvaine

AU - Maitre, Marlène

AU - Dedieu, Stéphane

AU - Jeanne, Albin

AU - Bailly, Sabine

AU - Feige, Jean Jacques

AU - Miletic, Hrvoje

AU - Rossi, Marco

AU - Bello, Lorenzo

AU - Falciani, Francesco

AU - Bjerkvig, Rolf

AU - Bikfalvi, Andréas

N1 - Funding Information: This work was supported by grants from INSERM (recurrent funding), and from the “Ligue contre le Cancer” to A.B. and by Helse Vest, Haukeland Hospital, The Norwegian Research Council and Stiftelsen Kristian Gerhard Jebsen Research Foundation for R.B. T.D. was a recipient of Norwegian Cancer Society. LCM facility is supported by LabEX BRAIN ANR-10-LABX-43 and FRM DGE20061007758. We thank A. Barre for first bioinformatics analysis of RNA-sequencing results. Library generation and sequencing were performed by L. Rainbow, C. Nelson and A. Lucaci, and the bioinformatics work was performed by R. Gregory at The Centre for Genomic Research, University of Liverpool and P. Koldkjaer for performing RNA-sequencing. We also thank M. Delugin, J. Massiere, M. Poulet and T. Chouleur for preliminary experiment, the Bordeaux Imaging Center for Nanozoomer use, M.P. Algeo, M.A. Derieppe, M. Campistron for animal treatments and care. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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VL - 10

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Deciphering the complex role of thrombospondin-1 in glioblastoma development

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