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

Laetitia Seguin, Soline Odouard, Francesca Corlazzoli, Sarah Al Haddad, Laurine Moindrot, Marta Calvo Tardón, Mayra Yebra, Alexey Koval, Eliana Marinari, Viviane Bes, Alexandre Guérin, Mathilde Allard, Sten Ilmjärv, Vladimir L. Katanaev, Paul R. Walker, Karl Heinz Krause, Valérie Dutoit, Jann N. Sarkaria, Pierre Yves Dietrich, Érika Cosset

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number718
JournalCommunications Biology
Volume4
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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