Deciphering the complex role of thrombospondin-1 in glioblastoma development
Thomas Daubon
(1, 2)
,
Céline Léon
(2)
,
Kim Clarke
(3)
,
Laetitia Andrique
(2)
,
Laura Salabert
(2)
,
Elodie Darbo
(4, 5)
,
Raphael Pineau
(6)
,
Sylvaine Guérit
(2)
,
Marlène Maitre
(7)
,
Stéphane Dedieu
(8)
,
Albin Jeanne
(8, 9)
,
Sabine Bailly
(10)
,
Jean-Jacques Feige
(10)
,
Hrvoje Miletic
(1, 11)
,
Marco Rossi
(12)
,
Lorenzo Bello
(12)
,
Francesco Falciani
(3)
,
Rolf Bjerkvig
(1, 13)
,
Andréas Bikfalvi
(2)
1
UiB -
University of Bergen
2 LAMC - Laboratoire Angiogenèse et Micro-environnement des Cancers
3 University of Liverpool
4 ACTION - Actions for OnCogenesis understanding and Target Identification in ONcology
5 CBIB - Centre de Bioinformatique de Bordeaux
6 UB - Université de Bordeaux
7 U1215 Inserm - UB - Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale
8 MEDyC - Matrice Extracellulaire et Dynamique Cellulaire - UMR CNRS 7369
9 SATT NORD - Société d’Accélération du Transfert de Technologie
10 BCI - Biologie du Cancer et de l'Infection
11 Haukeland University Hospital
12 UNIMI - Università degli Studi di Milano = University of Milan
13 LIH - Luxembourg Institute of Health
2 LAMC - Laboratoire Angiogenèse et Micro-environnement des Cancers
3 University of Liverpool
4 ACTION - Actions for OnCogenesis understanding and Target Identification in ONcology
5 CBIB - Centre de Bioinformatique de Bordeaux
6 UB - Université de Bordeaux
7 U1215 Inserm - UB - Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale
8 MEDyC - Matrice Extracellulaire et Dynamique Cellulaire - UMR CNRS 7369
9 SATT NORD - Société d’Accélération du Transfert de Technologie
10 BCI - Biologie du Cancer et de l'Infection
11 Haukeland University Hospital
12 UNIMI - Università degli Studi di Milano = University of Milan
13 LIH - Luxembourg Institute of Health
Thomas Daubon
- Fonction : Auteur
- PersonId : 737075
- IdHAL : thomas-daubon
- ORCID : 0000-0002-0319-7617
- IdRef : 135422906
Laetitia Andrique
- Fonction : Auteur
- PersonId : 758714
- ORCID : 0000-0001-7840-8135
Albin Jeanne
- Fonction : Auteur
- PersonId : 779511
- ORCID : 0000-0003-2930-4158
- IdRef : 184230942
Sabine Bailly
- Fonction : Auteur
- PersonId : 759262
- ORCID : 0000-0003-1043-7030
- IdRef : 078713293
Marco Rossi
- Fonction : Auteur
- PersonId : 757527
- ORCID : 0000-0002-0196-2370
Rolf Bjerkvig
- Fonction : Auteur
- PersonId : 795437
- ORCID : 0000-0002-9622-7263
Andréas Bikfalvi
- Fonction : Auteur
- PersonId : 759771
- ORCID : 0000-0003-4138-5229
Résumé
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.