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Deciphering the Action of Neuraminidase in Glioblastoma Models
Nathalie Baeza-Kallee1, Raphaël Bergès1, Victoria Hein1
1Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13005 Marseille, France.
Abstract:
Glioblastoma (GBM) contains cancer stem cells (CSC) that are resistant to treatment. GBM CSC expresses glycolipids recognized by the A2B5 antibody. A2B5, induced by the enzyme ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyl transferase 3 (ST8Sia3), plays a crucial role in the proliferation, migration, clonogenicity and tumorigenesis of GBM CSC. Our aim was to characterize the resulting effects of neuraminidase that removes A2B5 in order to target GBM CSC. To this end, we set up a GBM organotypic slice model; quantified A2B5 expression by flow cytometry in U87-MG, U87-ST8Sia3 and GBM CSC lines, treated or not by neuraminidase; performed RNAseq and DNA methylation profiling; and analyzed the ganglioside expression by liquid chromatography-mass spectrometry in these cell lines, treated or not with neuraminidase. Results demonstrated that neuraminidase decreased A2B5 expression, tumor size and regrowth after surgical removal in the organotypic slice model but did not induce a distinct transcriptomic or epigenetic signature in GBM CSC lines. RNAseq analysis revealed that OLIG2, CHI3L1, TIMP3, TNFAIP2, and TNFAIP6 transcripts were significantly overexpressed in U87-ST8Sia3 compared to U87-MG. RT-qPCR confirmed these results and demonstrated that neuraminidase decreased gene expression in GBM CSC lines. Moreover, neuraminidase drastically reduced ganglioside expression in GBM CSC lines. Neuraminidase, by its pleiotropic action, is an attractive local treatment against GBM.
Insights
Neuraminidase reduces A2B5 expression and glioblastoma growth in a slice model. This enzyme offers a promising therapeutic strategy by targeting cancer stem cells and decreasing ganglioside expression in GBM.
Area of Science:
- Neuro-oncology
- Cancer Stem Cell Biology
- Glycobiology
Background:
- Glioblastoma (GBM) cancer stem cells (CSCs) exhibit treatment resistance.
- A2B5 glycolipids, induced by ST8Sia3, are crucial for GBM CSC proliferation, migration, and tumorigenesis.
- Targeting A2B5 presents a potential therapeutic avenue for GBM.
Purpose of the Study:
- To investigate the effects of neuraminidase, an enzyme that removes A2B5, on GBM CSCs.
- To evaluate neuraminidase as a potential local treatment for GBM.
Main Methods:
- Utilized a GBM organotypic slice model.
- Quantified A2B5 expression via flow cytometry in GBM cell lines (U87-MG, U87-ST8Sia3, GBM CSCs) with and without neuraminidase treatment.
- Performed RNA sequencing, DNA methylation profiling, and liquid chromatography-mass spectrometry analysis of ganglioside expression.
Main Results:
- Neuraminidase decreased A2B5 expression, tumor size, and regrowth in the organotypic slice model.
- No distinct transcriptomic or epigenetic signature was induced by neuraminidase in GBM CSCs.
- RNAseq identified overexpression of OLIG2, CHI3L1, TIMP3, TNFAIP2, and TNFAIP6 in U87-ST8Sia3 cells.
- Neuraminidase treatment reduced gene expression and drastically decreased ganglioside expression in GBM CSCs.
Conclusions:
- Neuraminidase effectively reduces A2B5 expression and inhibits GBM growth in a preclinical model.
- Neuraminidase demonstrates pleiotropic actions, making it an attractive candidate for local GBM treatment.
- Targeting A2B5 with neuraminidase warrants further investigation for GBM therapy.
