Hein Victoria, Baeza-Kallee Nathalie, Bergès Raphaël, Essakhi Nora, Soubéran Aurélie, Colin Carole, Morando Philippe, Appay Romain, Graillon Thomas, Tchoghandjian Aurélie, Figarella-Branger Dominique, Tabouret Emeline
Inst Neurophysiopathol, Aix-Marseille Univ, CNRS, INP, GlioME Team, Marseille, France.
Réseau Préclinique et Translationnel de Recherche en Neuro-oncologie, Aix-Marseille Univ, Plateforme PETRA"TECH" and Plateforme PE"TRANSLA", Marseille, France.
Cancer Cell Int. 2025 Jul 2;25(1):246. doi: 10.1186/s12935-025-03790-2.
Glioblastoma is the most aggressive primary brain tumour with no curative treatment and inevitable relapse. Therapeutic resistance is, at least, related to the presence of cancer stem-like cells in these tumours. Here, we aimed to demonstrate that the GD3 ganglioside was a relevant marker and actionable target for glioblastoma cancer stem-like cells.
To this end, we used commercial glioblastoma cell lines, human glioblastoma samples, organotypic culture and xenografted mouse models to study GD3 antigen expression and consequences of its downregulation through a shRNA strategy targeting the ST8SIA1 mRNA which encodes the key enzyme for GD3 synthesis. We performed mono-dimensional Thin Layer Chromatography to analyse ganglioside composition of the glioblastoma samples and RNA-seq analyses to reveal oncogenic pathways and more specifically transcripts affected by ST8SIA1 silencing. Besides, we evaluated GD3 role in stemness of glioblastoma cancer cell, phenotype, microenvironment interaction, and invasion abilities.
We showed that GD3 is the main ganglioside in glioblastoma and that patient-derived cancer stem-like cell lines strongly expressed GD3. This GD3 + population decreased significantly after cell differentiation. GD3 cells sorted from patient samples had stem-like cell properties: they were plastic, clonogenic, and tumorigenic after orthotopic engraftment. Silencing of ST8SIA1/GD3 was associated with a decrease in sphere size, self-renewal and migratory capacities and increased mouse survival. Moreover, increased temozolomide sensitivity was recorded. Finally, data from RNA-seq showed that silencing ST8SIA1/GD3 decreased oncogenic pathways and more specifically the expression of ADAMTS1 and IL33 transcripts.
Taken together, our results suggest that GD3 ganglioside is essential for glioblastoma cancer stem-like cell properties, opening promising targeted therapeutic development.
胶质母细胞瘤是最具侵袭性的原发性脑肿瘤，尚无治愈性治疗方法且不可避免会复发。治疗耐药性至少与这些肿瘤中癌症干细胞样细胞的存在有关。在此，我们旨在证明GD3神经节苷脂是胶质母细胞瘤癌症干细胞样细胞的相关标志物和可作用靶点。
为此，我们使用了商业化的胶质母细胞瘤细胞系、人胶质母细胞瘤样本、器官型培养和异种移植小鼠模型，通过靶向编码GD3合成关键酶的ST8SIA1 mRNA的shRNA策略来研究GD3抗原表达及其下调的后果。我们进行了一维薄层色谱分析胶质母细胞瘤样本的神经节苷脂组成，并进行RNA测序分析以揭示致癌途径，更具体地说是受ST8SIA1沉默影响的转录本。此外，我们评估了GD3在胶质母细胞瘤癌细胞干性、表型、微环境相互作用和侵袭能力中的作用。
我们表明GD3是胶质母细胞瘤中的主要神经节苷脂，且患者来源的癌症干细胞样细胞系强烈表达GD3。细胞分化后，这群GD3阳性细胞显著减少。从患者样本中分选的GD3细胞具有干细胞样细胞特性：它们具有可塑性、克隆性，原位植入后具有致瘤性。ST8SIA1/GD3沉默与球体大小、自我更新和迁移能力的降低以及小鼠存活率的提高相关。此外，还记录到替莫唑胺敏感性增加。最后，RNA测序数据表明，沉默ST8SIA1/GD3可减少致癌途径，更具体地说是减少ADAMTS1和IL33转录本的表达。
综上所述，我们的结果表明GD3神经节苷脂对胶质母细胞瘤癌症干细胞样细胞特性至关重要，为有前景的靶向治疗开发开辟了道路。
