Deciphering the complex role of thrombospondin-1 in glioblastoma development

Thomas Daubon,Thomas Daubon,Thomas Daubon,Céline Léon,Céline Léon,Jean-Jacques Feige,Lorenzo Bello,Albin Jeanne,Albin Jeanne,Albin Jeanne,Albin Jeanne,Laetitia Andrique,Marlène Maitre,Raphael Pineau,Sylvaine Guérit,Sylvaine Guérit,Rolf Bjerkvig,Rolf Bjerkvig,Sabine Bailly,Francesco Falciani,Marco Rossi,Elodie Darbo,Laura Salabert,Laura Salabert,Andréas Bikfalvi,Andréas Bikfalvi,Hrvoje Miletic,Hrvoje Miletic,Stéphane Dedieu,Stéphane Dedieu,Stéphane Dedieu,Kim Clarke

doi:10.1038/s41467-019-08480-y

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.

Highlights

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
We have previously shown that THBS1 is expressed in tumour blood vessels and in specific patient-derived xenograft (PDX) models[14]
According to The Cancer Genome Atlas (TCGA), THBS1 expression is found to be increased in GBMs when compared to grade II and III tumours (Supplementary Fig. 1A), and linked to patient survival (Supplementary Fig. 1B)

Summary

Introduction

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. 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 Smad[3] which contributes to the invasive behaviour during GBM expansion. Our data show that THBS1 is involved in the regulation of angiogenesis in GBM, and impacts the invasive behaviour of glioma cells and that THBS1/ CD47 interactions contributes to this process. THBS1 was the gene with the highest connectivity in the peripheral tumour areas

Methods

Results

Conclusion