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- Title
Macropinocytosis requires Gal-3 in a subset of patient-derived glioblastoma stem cells.
- Authors
Seguin, Laetitia; Odouard, Soline; Corlazzoli, Francesca; Haddad, Sarah Al; Moindrot, Laurine; Calvo Tardón, Marta; Yebra, Mayra; Koval, Alexey; Marinari, Eliana; Bes, Viviane; Guérin, Alexandre; Allard, Mathilde; Ilmjärv, Sten; Katanaev, Vladimir L.; Walker, Paul R.; Krause, Karl-Heinz; Dutoit, Valérie; Sarkaria, Jann N.; Dietrich, Pierre-Yves; Cosset, Érika
- Abstract
Recently, we involved the carbohydrate-binding protein Galectin-3 (Gal-3) as a druggable target for KRAS-mutant-addicted lung and pancreatic cancers. Here, using glioblastoma patient-derived stem cells (GSCs), we identify and characterize a subset of Gal-3high glioblastoma (GBM) tumors mainly within the mesenchymal subtype that are addicted to Gal-3-mediated macropinocytosis. Using both genetic and pharmacologic inhibition of Gal-3, we showed a significant decrease of GSC macropinocytosis activity, cell survival and invasion, in vitro and in vivo. Mechanistically, we demonstrate that Gal-3 binds to RAB10, a member of the RAS superfamily of small GTPases, and β1 integrin, which are both required for macropinocytosis activity and cell survival. Finally, by defining a Gal-3/macropinocytosis molecular signature, we could predict sensitivity to this dependency pathway and provide proof-of-principle for innovative therapeutic strategies to exploit this Achilles' heel for a significant and unique subset of GBM patients. Seguin et al demonstrated in glioblastoma patient-derived stem cells that a subset of glioblastoma tumours is dependent on macropinocytosis mediated survival through a Galectin-3/RAB10/beta 1 integrin axis. They used both genetic and pharmacologic inhibition of Galectin-3 in vivo and in vitro to identify underlying mechanisms and define a Galectin-3/macropinocytosis molecular signature, which could inform the development of anti-tumour therapeutic strategies.
- Subjects
GLIOBLASTOMA multiforme; STEM cells; ACHILLES tendinitis; PHARMACOLOGY; GENETICS
- Publication
Communications Biology, 2021, Vol 4, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-021-02258-z