TY - JOUR
T1 - Exploring high-throughput drug sensitivity testing in neuroblastoma cell lines and patient-derived tumor organoids in the era of precision medicine
AU - Langenberg, Karin P.S.
AU - van Hooff, Sander R.
AU - Koopmans, Bianca
AU - Strijker, Josephine G.M.
AU - Kholosy, Waleed M.
AU - Ober, Kimberley
AU - Zwijnenburg, Danny A.
AU - van der Hoek, Jessica J.F.
AU - Keller, Kaylee M.
AU - Vernooij, Lindy
AU - Schild, Linda G.
AU - Looze, Eleonora J.
AU - Ebus, Marli E.
AU - Essing, Anke H.W.
AU - Vree, Paula de
AU - Tas, Michelle L.
AU - Matser, Yvette A.H.
AU - Wienke, Judith
AU - Volckmann, Richard
AU - Tops, Bastiaan B.J.
AU - Kester, Lennart A.
AU - Badloe, Shashi
AU - Hehir-Kwa, Jayne Y.
AU - Kemmeren, Patrick
AU - Goemans, Bianca F.
AU - Zwaan, C. Michel
AU - Oehme, Ina
AU - Jäger, Nathalie
AU - Witt, Olaf
AU - van Eijkelenburg, Natasha K.A.
AU - Dierselhuis, Miranda P.
AU - Tytgat, Godelieve A.M.
AU - Wijnen, Marc H.W.
AU - van Noesel, Max M.
AU - de Krijger, Ronald R.
AU - Eising, Selma
AU - Koster, Jan
AU - Dolman, Emmy M.
AU - Molenaar, Jan J.
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2025/3/11
Y1 - 2025/3/11
N2 - Introduction: Despite druggable events to be present in 80 % of neuroblastomapatients within the Princess Máxima Center precision medicine program 'iTHER', clinical uptake of treatment recommendations has been low, and the clinical impact for individual patients remains hard to predict. This stresses the need for a method integrating genomics and transcriptomics with functional approaches into therapeutic decision making. Methods: We aimed to launch an online repository integrating genomics and transcriptomics with high-throughput drug screening (HTS) of nineteen commonly used neuroblastoma cell lines and fifteen neuroblastoma patient-derived organoids (NBL-PDOs). Cell lines, NBL-PDOs and their parental tumors were characterized utilizing (lc)WGS, WES and RNAseq. Cells were exposed to ∼200 compounds. Results were transferred to the R2 visualization platform. Results: A powerful reference set of cell lines is available, reflecting distinct known pharmacologic vulnerabilities. HTS identified additional therapeutic vulnerabilities, such as a striking correlation between a positive mesenchymal signature and sensitivity to BCL2-inhibitor venetoclax. Finally, we explored personalized drug sensitivities within iTHER, demonstrating HTS can support genomic and transcriptomic results, thereby strengthening the rationale for clinical uptake. Conclusion: We established a dynamic publicly available dataset with detailed genomic, transcriptomic, and pharmacological annotation of classical neuroblastoma cell lines as well as novel sharable NBL-PDOs, representing the heterogeneous landscape of neuroblastoma. We anticipate that in vitro drug screening will be complementary to genomic-guided precision medicine by supporting clinical decision making, thereby improving prognosis for all neuroblastoma patients in the future.
AB - Introduction: Despite druggable events to be present in 80 % of neuroblastomapatients within the Princess Máxima Center precision medicine program 'iTHER', clinical uptake of treatment recommendations has been low, and the clinical impact for individual patients remains hard to predict. This stresses the need for a method integrating genomics and transcriptomics with functional approaches into therapeutic decision making. Methods: We aimed to launch an online repository integrating genomics and transcriptomics with high-throughput drug screening (HTS) of nineteen commonly used neuroblastoma cell lines and fifteen neuroblastoma patient-derived organoids (NBL-PDOs). Cell lines, NBL-PDOs and their parental tumors were characterized utilizing (lc)WGS, WES and RNAseq. Cells were exposed to ∼200 compounds. Results were transferred to the R2 visualization platform. Results: A powerful reference set of cell lines is available, reflecting distinct known pharmacologic vulnerabilities. HTS identified additional therapeutic vulnerabilities, such as a striking correlation between a positive mesenchymal signature and sensitivity to BCL2-inhibitor venetoclax. Finally, we explored personalized drug sensitivities within iTHER, demonstrating HTS can support genomic and transcriptomic results, thereby strengthening the rationale for clinical uptake. Conclusion: We established a dynamic publicly available dataset with detailed genomic, transcriptomic, and pharmacological annotation of classical neuroblastoma cell lines as well as novel sharable NBL-PDOs, representing the heterogeneous landscape of neuroblastoma. We anticipate that in vitro drug screening will be complementary to genomic-guided precision medicine by supporting clinical decision making, thereby improving prognosis for all neuroblastoma patients in the future.
KW - Adolescent
KW - Cancer
KW - Child
KW - High-throughput drug screening
KW - Molecular biology
KW - Molecular targeted therapy
KW - Neuroblastoma
KW - Next-generation sequencing
KW - Organoid
KW - Precision medicine
UR - http://www.scopus.com/inward/record.url?scp=85217900135&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2025.115275
DO - 10.1016/j.ejca.2025.115275
M3 - Article
AN - SCOPUS:85217900135
SN - 0959-8049
VL - 218
JO - European Journal of Cancer
JF - European Journal of Cancer
M1 - 115275
ER -