TGF-β-induced ganglioside remodeling highlights GD2 as a dynamically regulated target in glioblastoma

Glioblastoma (GBM) is characterized by extensive cellular plasticity and dynamic interactions with the tumor microenvironment. The tumor-associated ganglioside GD2 is considered a promising therapeutic target, although its stability across different cellular states remains unclear. Here, we investigated whether transforming growth factor-β (TGF-β), a key regulator of glioblastoma progression and mesenchymal reprogramming, modulates ganglioside-biosynthetic gene expression and GD2 surface expression.

Using U87-MG and U251-MG glioblastoma cell lines, we combined MALDI–TOF-MS glycosphingolipid profiling, flow cytometry, quantitative PCR, Western blot analysis, and migration assays to characterize TGF-β–induced phenotypic changes. Baseline analyses revealed marked differences in ganglioside composition between the two cell lines. TGF-β induced distinct mesenchymal-like phenotypic responses and differentially regulated ganglioside-biosynthetic gene expression, resulting in opposite effects on GD2 surface expression: GD2 levels increased in U251-MG cells but decreased in U87-MG cells.

These changes were accompanied by cell line–specific alterations in migratory behavior. Pharmacological inhibition of UDP-glucose ceramide glucosyltransferase (UGCG) reduced GD2 expression and attenuated migration, supporting a broader contribution of glycosphingolipid biosynthesis to migratory behavior. Together, these findings demonstrate that GD2 expression is dynamically regulated by microenvironmental signaling and is associated with TGF-β-induced phenotypic changes in the glioblastoma cell models examined.

Our results identify changes in ganglioside-biosynthetic gene expression and GD2 surface abundance as molecular features accompanying tumor cell plasticity and suggest that GD2 should be considered a context-dependent therapeutic target rather than a stable tumor-associated marker. The authors would like to thank the UGSF laboratory (CNRS UMR 8576, Université de Lille) for providing the research environment and infrastructure that made this study possible. We also gratefully acknowledge the Université de Lille for providing the opportunity to conduct this research through the MOBLILEX mobility programme, as well as Campus France Hongrie and the Embassy of France in Hungary for their support of international academic mobility and research collaboration.

This work was supported by the MOBLILEX mobility programme, which enabled a research stay at Université de Lille, the Campus France Excellence Scholarship, and the Semmelweis 250 + Excellence Ph.D. Department of Pharmacodynamics, Semmelweis University, 4 Nagyvárad tér, Budapest, H-1089, Hungary Katinka Tarnóczi, Alexandra Paszternák, Tamás Tábi & Éva Szökő Center for Pharmacology and Drug Research & Development, Semmelweis University, 26 Üllői út, Budapest, H-1085, Hungary Alexandra Paszternák, Tamás Tábi & Éva Szökő CNRS, UMR 8576—UGSF—Unité de Glycobiologie Structurale et Fonctionnelle, University of Lille, Lille, F-59000, France Katinka Tarnóczi, Clara Siddi, Maxime Grember, Clément Delannoy, Fabrice Allain, Agnes Denys, Yann Guerardel, Marie-Ange Krzewinski-Recchi & Sophie Groux-Degroote INSERM U1366, CNRS UMR 9020, University of Lille, CRCLille Lab., CHU Lille, ONCOLille Interdisciplinary Cancer Research Institute, Lille, France CNRS, IRL 2045, GlycoMIRAL, Nagoya University, Nagoya, Japan The authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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