{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T14:33:43Z","timestamp":1777646023733,"version":"3.51.4"},"reference-count":30,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T00:00:00Z","timestamp":1709596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002809","name":"Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya","doi-asserted-by":"publisher","award":["2023SGR 015452"],"award-info":[{"award-number":["2023SGR 015452"]}],"id":[{"id":"10.13039\/501100002809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002809","name":"Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya","doi-asserted-by":"publisher","award":["PID2020-117977RA-I00"],"award-info":[{"award-number":["PID2020-117977RA-I00"]}],"id":[{"id":"10.13039\/501100002809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Biomedical Research Networking (CIBER), Spain","award":["2023SGR 015452"],"award-info":[{"award-number":["2023SGR 015452"]}]},{"name":"Biomedical Research Networking (CIBER), Spain","award":["PID2020-117977RA-I00"],"award-info":[{"award-number":["PID2020-117977RA-I00"]}]},{"name":"Spanish Association Against Cancer (AECC)","award":["2023SGR 015452"],"award-info":[{"award-number":["2023SGR 015452"]}]},{"name":"Spanish Association Against Cancer (AECC)","award":["PID2020-117977RA-I00"],"award-info":[{"award-number":["PID2020-117977RA-I00"]}]},{"name":"Association of Families and Friends of Children with Neuroblastoma (NEN)","award":["2023SGR 015452"],"award-info":[{"award-number":["2023SGR 015452"]}]},{"name":"Association of Families and Friends of Children with Neuroblastoma (NEN)","award":["PID2020-117977RA-I00"],"award-info":[{"award-number":["PID2020-117977RA-I00"]}]},{"DOI":"10.13039\/501100011033","name":"Spanish National R+D+I plan","doi-asserted-by":"publisher","award":["2023SGR 015452"],"award-info":[{"award-number":["2023SGR 015452"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Spanish National R+D+I plan","doi-asserted-by":"publisher","award":["PID2020-117977RA-I00"],"award-info":[{"award-number":["PID2020-117977RA-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers16051060","type":"journal-article","created":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T08:35:54Z","timestamp":1709627754000},"page":"1060","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of GB3 as a Novel Biomarker of Tumor-Derived Vasculature in Neuroblastoma Using a Stiffness-Based Model"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7919-9670","authenticated-orcid":false,"given":"Aranzazu","family":"Villasante","sequence":"first","affiliation":[{"name":"Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain"},{"name":"Department of Electronic and Biomedical Engineering, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josep","family":"Corominas","sequence":"additional","affiliation":[{"name":"Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Alcon","sequence":"additional","affiliation":[{"name":"Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-2093","authenticated-orcid":false,"given":"Andrea","family":"Garcia-Lizarribar","sequence":"additional","affiliation":[{"name":"Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain"},{"name":"Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9386-5980","authenticated-orcid":false,"given":"Jaume","family":"Mora","sequence":"additional","affiliation":[{"name":"Oncology Department, Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, 08950 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4754-311X","authenticated-orcid":false,"given":"Monica","family":"Lopez-Fanarraga","sequence":"additional","affiliation":[{"name":"University of Cantabria-IDIVAL, 39011 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1140-3679","authenticated-orcid":false,"given":"Josep","family":"Samitier","sequence":"additional","affiliation":[{"name":"Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain"},{"name":"Department of Electronic and Biomedical Engineering, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16078","DOI":"10.1038\/nrdp.2016.78","article-title":"Neuroblastoma","volume":"2","author":"Matthay","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Gautier, M., Thirant, C., Delattre, O., and Janoueix-Lerosey, I. (2021). Plasticity in Neuroblastoma Cell Identity Defines a Noradrenergic-to-Mesenchymal Transition (NMT). Cancers, 13.","DOI":"10.3390\/cancers13122904"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1177\/1535370220949237","article-title":"An Overview of Neuroblastoma Cell Lineage Phenotypes and in Vitro Models","volume":"245","author":"Cavalli","year":"2020","journal-title":"Exp. Biol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1593\/neo.04310","article-title":"Characteristics of Stem Cells from Human Neuroblastoma Cell Lines and in Tumors","volume":"6","author":"Walton","year":"2004","journal-title":"Neoplasia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"782","DOI":"10.3389\/fendo.2019.00782","article-title":"Cancer Stem Cells and Neuroblastoma: Characteristics and Therapeutic Targeting Options","volume":"10","author":"Veschi","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1038\/ng.3921","article-title":"Heterogeneity of Neuroblastoma Cell Identity Defined by Transcriptional Circuitries","volume":"49","author":"Boeva","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/ng.3899","article-title":"Neuroblastoma Is Composed of Two Super-Enhancer-Associated Differentiation States","volume":"49","author":"Koster","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/ijc.30067","article-title":"Tumour Angiogenesis-Origin of Blood Vessels","volume":"139","author":"Nagare","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Belotti, D., Pinessi, D., and Taraboletti, G. (2021). Alternative Vascularization Mechanisms in Tumor Resistance to Therapy. Cancers, 13.","DOI":"10.3390\/cancers13081912"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1006\/mvre.1996.0025","article-title":"Intussusceptive Microvascular Growth in a Human Colon Adenocarcinoma Xenograft: A Novel Mechanism of Tumor Angiogenesis","volume":"51","author":"Patan","year":"1996","journal-title":"Microvasc. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1200\/JCO.2006.09.0696","article-title":"Tumor Origin of Endothelial Cells in Human Neuroblastoma","volume":"25","author":"Pezzolo","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4099","DOI":"10.7150\/thno.20730","article-title":"Vascularized Tissue-Engineered Model for Studying Drug Resistance in Neuroblastoma","volume":"7","author":"Villasante","year":"2017","journal-title":"Theranostics"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Liu, H.-L., Tang, H., Yang, H., Deng, T.-T., Xu, Y.-P., Xu, S.-Q., Peng, L., Wang, Z., Fang, Q., and Kuang, X.-Y. (2020). Oct4 Regulates the Transition of Cancer Stem-Like Cells to Tumor Endothelial-Like Cells in Human Liver Cancer. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.563316"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1038\/cr.2011.38","article-title":"Oct-4+\/Tenascin C+ Neuroblastoma Cells Serve as Progenitors of Tumor-Derived Endothelial Cells","volume":"21","author":"Pezzolo","year":"2011","journal-title":"Cell Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Celi, A.B., Goldstein, J., Rosato-Siri, M.V., and Pinto, A. (2022). Role of Globotriaosylceramide in Physiology and Pathology. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.813637"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Desselle, A., Chaumette, T., Gaugler, M.-H., Cochonneau, D., Fleurence, J., Dubois, N., Hulin, P., Aubry, J., Birkl\u00e9, S., and Paris, F. (2012). Anti-Gb3 Monoclonal Antibody Inhibits Angiogenesis and Tumor Development. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045423"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.stem.2018.02.009","article-title":"Vascular Tissue Engineering: Progress, Challenges, and Clinical Promise","volume":"22","author":"Song","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2100798","DOI":"10.1002\/advs.202100798","article-title":"In Vitro Strategies to Vascularize 3D Physiologically Relevant Models","volume":"8","author":"Dellaquila","year":"2021","journal-title":"Adv. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.actbio.2019.07.030","article-title":"Substrate Stiffness Directs Diverging Vascular Fates","volume":"96","author":"Wong","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1016\/j.bbamcr.2017.07.006","article-title":"Substrate Stiffness Regulates Arterial-Venous Differentiation of Endothelial Progenitor Cells via the Ras\/Mek Pathway","volume":"1864","author":"Xue","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Cell Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.trsl.2021.06.006","article-title":"Horizontal Transfer of the Stemness-Related Markers EZH2 and GLI1 by Neuroblastoma-Derived Extracellular Vesicles in Stromal Cells","volume":"237","author":"Villasante","year":"2021","journal-title":"Transl. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.biotechadv.2018.02.005","article-title":"Intracellular Drug Delivery: Potential Usefulness of Engineered Shiga Toxin Subunit B for Targeted Cancer Therapy","volume":"36","author":"Luginbuehl","year":"2018","journal-title":"Biotechnol. Adv."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Navarro-Palomares, E., Garc\u00eda-Hevia, L., Pad\u00edn-Gonz\u00e1lez, E., Ba\u00f1obre-L\u00f3pez, M., Villegas, J.C., Valiente, R., and Fanarraga, M.L. (2021). Targeting Nanomaterials to Head and Neck Cancer Cells Using a Fragment of the Shiga Toxin as a Potent Natural Ligand. Cancers, 13.","DOI":"10.3390\/cancers13194920"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5747","DOI":"10.2147\/IJN.S381628","article-title":"Shiga Toxin-B Targeted Gold Nanorods for Local Photothermal Treatment in Oral Cancer Clinical Samples","volume":"17","author":"Gandarillas","year":"2022","journal-title":"Int. J. Nanomed."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15406","DOI":"10.1021\/acsomega.3c00667","article-title":"Clickable Shiga Toxin B Subunit for Drug Delivery in Cancer Therapy","volume":"8","author":"Danielewicz","year":"2023","journal-title":"ACS Omega"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"684","DOI":"10.3389\/fphys.2020.00684","article-title":"The Importance of Mechanical Forces for in Vitro Endothelial Cell Biology","volume":"11","author":"Gordon","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"120","DOI":"10.22203\/eCM.v026a09","article-title":"Cell-Scaffold Interactions in the Bone Tissue Engineering Triad","volume":"26","author":"Murphy","year":"2013","journal-title":"Eur. Cells Mater."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0304-3835(03)00082-X","article-title":"The Regulation of Angiogenesis in Neuroblastoma","volume":"197","author":"Chlenski","year":"2003","journal-title":"Cancer Lett."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Strainiene, E., Binkis, M., Urnikyte, S., Stankevicius, V., Sasnauskiene, A., Kundrotas, G., Kazlauskas, A., and Suziedelis, K. (2018). Microenvironment Dependent Gene Expression Signatures in Reprogrammed Human Colon Normal and Cancer Cell Lines. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4145-8"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e23700","DOI":"10.4161\/onci.23700","article-title":"Inhibition of Tumor Angiogenesis by Globotriaosylceramide Immunotargeting","volume":"2","author":"Desselle","year":"2013","journal-title":"OncoImmunology"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/5\/1060\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:09:33Z","timestamp":1760105373000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/5\/1060"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,5]]},"references-count":30,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["cancers16051060"],"URL":"https:\/\/doi.org\/10.3390\/cancers16051060","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,5]]}}}