Journal
SCIENCE ADVANCES
Volume 8, Issue 43, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abq4617
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Funding
- Swedish Cancer Society [20 0897 PjF]
- Swedish Cancer Society postdoctoral fellowship [21 0346 PT]
- Swedish Childhood Cancer Foundation [PR2020-0018]
- Swedish Research Council [2021-02597]
- Crafoord Foundation [20210593]
- Region Skane and Skane University Hospital Funding grant
- Swedish Research Council [2021-02597] Funding Source: Swedish Research Council
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This study investigates the mechanisms of chemotherapy resistance in high-risk neuroblastoma (NB) and highlights the significance of transcriptional cell states in chemoresistance.
Chemotherapy resistance and relapses are common in high-risk neuroblastoma (NB). Here, we developed a clini-cally 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 asso-ciated 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 multi-potent Schwann cell precursors. NBs with a favorable treatment response presented a lineage-committed adren-ergic 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 re-sponse and emphasizes the importance of transcriptional cell states in chemoresistance.
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