Galectin-1 as a central regulator of angiogenesis and metabolic reprogramming in glioblastoma

Glioblastoma (GB) is the most aggressive tumor of the central nervous system characterized by rapid growth and remarkable resistance to current therapies. Its biology is shaped by profound inter- and intra-tumoral heterogeneity, a highly immunosuppressive microenvironment, and a strong dependence on metabolic and vascular adaptations that allow tumor cells to thrive under hypoxic and nutrient-poor conditions. A subpopulation enriched in glioma stem-like cells (GSCs) plays a central role in these adaptations, sustaining tumor expansion through flexible metabolic and angiogenic programs. Galectin-1 (GAL1), a glycan-binding lectin with multiple roles in the tumor microenvironment, is considerably elevated in gliomas. This led us to investigate whether GAL1 could act as a common regulator of both metabolism and angiogenesis in GB. We established patient-derived GSC lines (G02, G03, G08, G09), a model that preserves the clinical heterogeneity typical of this disease. RNA-seq and functional assays revealed clear differences among cell lines. G02 showed an endothelial-like signature and promoted endothelial cell migration, while G03 was enriched in angiogenesis-related pathways and formed robust tube-like structures in vitro, in line with higher VEGF secretion (p<0.01). Biopsies from the corresponding patients (G02 and G03) recapitulated this biology, displaying broad areas of microvascular proliferation. Inhibition of GAL1 with antibodies or siRNA reduced tube formation mainly in G03, suggesting that not all angiogenic profiles are likely dependent on GAL1. Metabolic analysis further supported this idea. Seahorse analysis showed that G02 and G03 respond to GAL1 depletion by shifting toward opposite metabolic programs, and complementary assays (TMRE, MitoSOX) revealed high mitochondrial activity in G02 (FC=2), while G09 displayed impaired OXPHOS (FC=0.5). Together, our data indicate that both secreted and intracellular GAL1 contribute to the metabolic and angiogenic adaptations that sustain GB growth. These results emphasize that GSCs rely on distinct yet coordinated strategies to obtain resources, and position GAL1 as a central regulator of these processes. Defining the cellular and functional profiles that determine sensitivity to GAL1 inhibition may help guide the development of more precise anti-angiogenic or metabolic therapies for glioblastoma.