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

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-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.

Abstract

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.