Macropinocytosis requires Gal-3 in a subset of patient-derived glioblastoma stem cells

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

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-3(high) 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.