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Article Dans Une Revue Neuro-Oncology Année : 2021

TGF-β promotes microtube formation in glioblastoma through thrombospondin 1

Justin Joseph
  • Fonction : Auteur
Capucine Magaut
  • Fonction : Auteur
Simon Storevik
  • Fonction : Auteur
Md Abdul Latif
  • Fonction : Auteur
Justine Rudewicz
  • Fonction : Auteur
Joris Guyon
Matteo Gambaretti
  • Fonction : Auteur
Frida Haukas
  • Fonction : Auteur
Amalie Trones
  • Fonction : Auteur
Lars Rømo Ystaas
  • Fonction : Auteur
Jubayer Hossain
  • Fonction : Auteur
Sandra Ninzima
  • Fonction : Auteur
Sylvain Cuvellier
  • Fonction : Auteur
Wenjing Zhou
  • Fonction : Auteur
Tushar Tomar
  • Fonction : Auteur
Barbara Klink
Lalit Rane
  • Fonction : Auteur
Bronwyn Irving
  • Fonction : Auteur
Joanne Marrison
  • Fonction : Auteur
Peter O’toole
  • Fonction : Auteur
Heiko Wurdak
  • Fonction : Auteur
Jian Wang
  • Fonction : Auteur
Zhang Di
  • Fonction : Auteur
Even Birkeland
  • Fonction : Auteur
Frode Berven
  • Fonction : Auteur
Frank Winkler
  • Fonction : Auteur
Frank Kruyt
  • Fonction : Auteur
Andreas Bikfalvi
Rolf Bjerkvig
Hrvoje Miletic
  • Fonction : Auteur

Résumé

Abstract Background Microtubes (MTs), cytoplasmic extensions of glioma cells, are important cell communication structures promoting invasion and treatment resistance through network formation. MTs are abundant in chemoresistant gliomas, in particular, glioblastomas (GBMs), while they are uncommon in chemosensitive IDH-mutant and 1p/19q co-deleted oligodendrogliomas. The aim of this study was to identify potential signaling pathways involved in MT formation. Methods Bioinformatics analysis of TCGA was performed to analyze differences between GBM and oligodendroglioma. Patient-derived GBM stem cell lines were used to investigate MT formation under transforming growth factor-beta (TGF-β) stimulation and inhibition in vitro and in vivo in an orthotopic xenograft model. RNA sequencing and proteomics were performed to detect commonalities and differences between GBM cell lines stimulated with TGF-β. Results Analysis of TCGA data showed that the TGF-β pathway is highly activated in GBMs compared to oligodendroglial tumors. We demonstrated that TGF-β1 stimulation of GBM cell lines promotes enhanced MT formation and communication via calcium signaling. Inhibition of the TGF-β pathway significantly reduced MT formation and its associated invasion in vitro and in vivo. Downstream of TGF-β, we identified thrombospondin 1 (TSP1) as a potential mediator of MT formation in GBM through SMAD activation. TSP1 was upregulated upon TGF-β stimulation and enhanced MT formation, which was inhibited by TSP1 shRNAs in vitro and in vivo. Conclusion TGF-β and its downstream mediator TSP1 are important mediators of the MT network in GBM and blocking this pathway could potentially help to break the complex MT-driven invasion/resistance network.

Domaines

Cancer

Dates et versions

hal-03442147 , version 1 (23-11-2021)

Identifiants

Citer

Justin Joseph, Capucine Magaut, Simon Storevik, Luiz Geraldo, Thomas Mathivet, et al.. TGF-β promotes microtube formation in glioblastoma through thrombospondin 1. Neuro-Oncology, 2021, ⟨10.1093/neuonc/noab212⟩. ⟨hal-03442147⟩

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