Clinically relevant treatment of PDX models reveals patterns of neuroblastoma chemoresistance

Adriana Mañas, Kristina Aaltonen, Natalie Andersson, Karin Hansson, Aleksandra Adamska, Alexandra Seger, Hiroaki Yasui, Hilda van den Bos, Katarzyna Radke, Javanshir Esfandyari, Madhura Satish Bhave, Jenny Karlsson, Diana Spierings, Floris Foijer, David Gisselsson, Daniel Bexell*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Chemotherapy resistance and relapses are common in high-risk neuroblastoma (NB). Here, we developed a clinically relevant in vivo treatment protocol mimicking the first-line five-chemotherapy treatment regimen of high-risk NB and applied this protocol to mice with MYCN-amplified NB patient-derived xenografts (PDXs). Genomic and transcriptomic analyses were used to reveal NB chemoresistance mechanisms. Intrinsic resistance was associated with high genetic diversity and an embryonic phenotype. Relapsed NB with acquired resistance showed a decreased adrenergic phenotype and an enhanced immature mesenchymal-like phenotype, resembling multipotent Schwann cell precursors. NBs with a favorable treatment response presented a lineage-committed adrenergic phenotype similar to normal neuroblasts. Novel integrated phenotypic gene signatures reflected treatment response and patient prognosis. NB organoids established from relapsed PDX tumors retained drug resistance, tumorigenicity, and transcriptional cell states. This work sheds light on the mechanisms of NB chemotherapy response and emphasizes the importance of transcriptional cell states in chemoresistance.

Original languageEnglish
Article numbereabq4617
Number of pages20
JournalScience Advances
Issue number43
Publication statusPublished - 28-Oct-2022

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