TGF-β promotes microtube formation in glioblastoma through thrombospondin 1
| Autor: | Tushar Tomar, Barbara Klink, Rolf Bjerkvig, Lars A. Rømo Ystaas, Zhang Di, Frida Haukas, Heiko Wurdak, Justine Rudewicz, Frode S. Berven, Amalie Trones, Lalit Rane, Justin V. Joseph, Even Birkeland, Sylvain Cuvellier, Frank Winkler, Frank A.E. Kruyt, Peter O'Toole, Jubayer A Hossain, Jian Wang, Matteo Gambaretti, Joanne Marrison, Thomas Mathivet, Andreas Bikfalvi, Wenjing Zhou, Hrvoje Miletic, Thomas Daubon, Bronwyn K. Irving, Sandra Ninzima, Simon Storevik, Luiz H. Geraldo, Capucine R. Magaut, Abdul Latif, Joris Guyon |
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| Přispěvatelé: | Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Damage and Repair in Cancer Development and Cancer Treatment (DARE) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
TGF-β
Cancer Research Cell signaling microtubes [SDV.CAN]Life Sciences [q-bio]/Cancer SMAD Tsp1 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation In vivo Glioma Thrombospondin 1 medicine 030304 developmental biology 0303 health sciences Chemistry glioblastoma medicine.disease nervous system diseases Oncology Cell culture 030220 oncology & carcinogenesis Cancer research Neurology (clinical) Signal transduction |
| Zdroj: | Neuro-Oncology Neuro-Oncology, Oxford University Press (OUP), 2021, ⟨10.1093/neuonc/noab212⟩ Joseph, J V, Magaut, C R, Storevik, S, Geraldo, L H, Mathivet, T, Latif, M A, Rudewicz, J, Guyon, J, Gambaretti, M, Haukas, F, Trones, A, Rømo Ystaas, L A, Hossain, J A, Ninzima, S, Cuvellier, S, Zhou, W, Tomar, T, Klink, B, Rane, L, Irving, B K, Marrison, J, O'Toole, P, Wurdak, H, Wang, J, Di, Z, Birkeland, E, Berven, F S, Winkler, F, Kruyt, F A E, Bikfalvi, A, Bjerkvig, R, Daubon, T & Miletic, H 2022, ' TGF-β promotes microtube formation in glioblastoma through thrombospondin 1 ', Neuro-Oncology, vol. 24, no. 4, pp. 541-553 . https://doi.org/10.1093/neuonc/noab212 Neuro-Oncology, 24(4). Oxford University Press |
| ISSN: | 1522-8517 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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