Exploring the role of sialidases in Galectin-1-associated resistance to cancer therapies
Scheidegger, Marco A. Merlo, Joaquín P. Villarreal, Santiago N. Schattner, Mirta Dalotto-Moreno, Tomás Mariño, Karina V. Rabinovich, Gabriel A.
Scheidegger, Marco A.
Merlo, Joaquín P.
Villarreal, Santiago N.
Schattner, Mirta
Dalotto-Moreno, Tomás
Mariño, Karina V.
Rabinovich, Gabriel A.
Type
Artículo de publicación periódica
Abstract
"The diverse repertoire of cell surface glycans, generated by the coordinated activity of glycosyltransferases and glycosidases, encodes critical biological information that is interpreted by glycan-binding proteins including galectins. Galectin-1 (GAL1), a member of this family, plays key roles across multiple hallmarks of cancer, including angiogenesis and immune evasion, driving resistance to anti-angiogenic and immunotherapeutic strategies through glycosylation-dependent mechanisms. Here, we first review the contribution of GAL1–glycan interactions to therapeutic resistance in cancer, with a particular focus on anti-angiogenic therapies and immunotherapy, and discuss the central role of glycosyltransferases in shaping these responses. While the biosynthesis of ‘GAL1-permissive’ glycans has been extensively characterized, the contribution of post-synthetic glycan remodeling to GAL1-driven therapeutic resistance remains uncertain. To explore mechanisms underlying GAL1-mediated resistance, we investigated whether tumor- or stromal-derived sialidases (NEU1 or NEU3) modulate sensitivity to vascular endothelial growth factor (VEGF)–targeted therapies by unmasking GAL1-binding glyco-epitopes. In the second part of the study, we present original in vivo experiments using gain- and loss-of-function approaches, demonstrating that, at least in our experimental settings, sialidases do not contribute to resistance to anti-VEGF treatment. Finally, bioinformatic analyses of patient datasets revealed differential regulation of GAL1, as well as specific glycosyltransferases, in patients responding or not to anti-VEGF or anti-PD-1 therapies. Collectively, these findings indicate that glycosyltransferases, particularly MGAT5, GCNT1, and ST6GAL1, coordinately shape the GAL1-specific glycome in settings of therapeutic resistance, whereas glycan remodeling by endogenous sialidases does not play a major role. Whether sialidases influence GAL1-dependent functions in other contexts remains to be explored".
Description
Date
2026-06
Journal Title
Journal ISSN
Volume Title
Publisher
Biochimica et Biophysica Acta (BBA) - General Subjects
Collections
Research Projects
Organizational Units
Journal Issue
Keywords
GALECTINA-1, SIALIDASAS, RESISTENCIA A TERAPIAS ONCOLÓGICAS, GLICOSILACIÓN, MICROAMBIENTE TUMORAL, ANTIANGIOGÉNESIS, INMUNOTERAPIA, GLICOTRANSFERASAS, VEGF, CÁNCER
Citation
Scheidegger, M. A., Merlo, J. P., Villarreal, S. N., Schattner, M., Croci, D. O., Dalotto-Moreno, T., Mariño, K. V., & Rabinovich, G. A. (2026). Exploring the role of sialidases in Galectin-1-associated resistance to cancer therapies. Biochimica et Biophysica Acta (BBA) - General Subjects, 1870(6), 130931. https://doi.org/10.1016/j.bbagen.2026.130931