GB3 as a novel therapeutic target in neuroblastoma's alternative vasculature through stiffness modeling

Neuroblastoma (NB) is a childhood cancer from sympathetic nervous system cells. NB exhibits cellular heterogeneity, with N, S, and I-type cells displaying distinct tumorigenic potentials. NB is highly vascularized, and blood vessels can form through various mechanisms, including endothelial transdifferentiation, leading to the development of tumor-derived endothelial cells (TECs) associated with chemoresistance. We lack specific biomarkers for TECs, relying mainly on general endothelial- expressed proteins like CD31 or stemness-related markers, which are crucial for the survival of healthy cells. Therefore, identifying new TEC biomarkers is vital for effective NB therapies. A stiffness-based platform simulating human arterial and venous stiffness was developed to study neuroblastoma TECs in vitro. N and I-type cells cultured on arterial-like stiffness transdifferentiated into TECs, while S-type cells did not. We employed TECs derived from N-type NB cells as a model to explore new TEC markers. Our focus was on Gb3, a glycosphingolipid receptor, which is overexpressed in some cancers and correlates with angiogenesis, metastasis, and drug resistance. Remarkably, we found that TECs expressed Gb3, confirming Gb3 as a novel marker for TECs and opening possibilities for targeted therapeutic intervention.