Identification of GB3 as a Novel Biomarker of Tumor-Derived Vasculature in Neuroblastoma Using a Stiffness-Based Model

Author:

Villasante Aranzazu123ORCID,Corominas Josep1,Alcon Clara1,Garcia-Lizarribar Andrea13ORCID,Mora Jaume4ORCID,Lopez-Fanarraga Monica5ORCID,Samitier Josep123ORCID

Affiliation:

1. Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain

2. Department of Electronic and Biomedical Engineering, University of Barcelona, 08028 Barcelona, Spain

3. Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain

4. Oncology Department, Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, 08950 Barcelona, Spain

5. University of Cantabria-IDIVAL, 39011 Santander, Spain

Abstract

Neuroblastoma (NB) is a childhood cancer in sympathetic nervous system cells. NB exhibits cellular heterogeneity, with adrenergic and mesenchymal states 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. 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 NB TECs in vitro. Adrenergic cells cultured on arterial-like stiffness transdifferentiated into TECs, while mesenchymal state cells did not. The TECs derived from adrenergic cells served as a model to explore new biomarkers, with a particular focus on GB3, a glycosphingolipid receptor implicated in angiogenesis, metastasis, and drug resistance. Notably, the TECs unequivocally expressed GB3, validating its novelty as a marker. To explore targeted therapeutic interventions, nanoparticles functionalized with the non-toxic subunit B of the Shiga toxin were generated, because they demonstrated a robust affinity for GB3-positive cells. Our results demonstrate the value of the stiffness-based platform as a predictive tool for assessing NB aggressiveness, the discovery of new biomarkers, and the evaluation of the effectiveness of targeted therapeutic strategies.

Funder

Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya

Biomedical Research Networking (CIBER), Spain

Spanish Association Against Cancer

Association of Families and Friends of Children with Neuroblastoma

Spanish National R+D+I plan

Publisher

MDPI AG

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