TY - JOUR
T1 - Macropinocytosis requires Gal-3 in a subset of patient-derived glioblastoma stem cells
AU - Seguin, Laetitia
AU - Odouard, Soline
AU - Corlazzoli, Francesca
AU - Haddad, Sarah Al
AU - Moindrot, Laurine
AU - Calvo Tardón, Marta
AU - Yebra, Mayra
AU - Koval, Alexey
AU - Marinari, Eliana
AU - Bes, Viviane
AU - Guérin, Alexandre
AU - Allard, Mathilde
AU - Ilmjärv, Sten
AU - Katanaev, Vladimir L.
AU - Walker, Paul R.
AU - Krause, Karl Heinz
AU - Dutoit, Valérie
AU - Sarkaria, Jann N.
AU - Dietrich, Pierre Yves
AU - Cosset, Érika
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s42003-021-02258-z
DO - 10.1038/s42003-021-02258-z
M3 - Article
C2 - 34112916
AN - SCOPUS:85107527684
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 718
ER -