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Clinically relevant treatment of PDX models reveals patterns of neuroblastoma chemoresistance

Mañas, Adriana LU ; Aaltonen, Kristina LU ; Andersson, Natalie LU orcid ; Hansson, Karin LU ; Adamska, Aleksandra LU ; Seger, Alexandra LU orcid ; Yasui, Hiroaki LU ; van den Bos, Hilda ; Radke, Katarzyna LU and Esfandyari, Javanshir LU , et al. (2022) In Science Advances 8(43).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Advances
volume
8
issue
43
article number
eabq4617
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:36306349
  • scopus:85141003573
ISSN
2375-2548
DOI
10.1126/sciadv.abq4617
project
Deciphering and targeting metastatic neuroblastoma treatment resistance
language
English
LU publication?
yes
id
12f99887-a00d-48ad-b174-3781cad650de
date added to LUP
2022-10-31 16:55:27
date last changed
2024-06-13 09:42:01
@article{12f99887-a00d-48ad-b174-3781cad650de,
  abstract     = {{<p>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 <br>
 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.<br>
 </p>}},
  author       = {{Mañas, Adriana and Aaltonen, Kristina and Andersson, Natalie and Hansson, Karin and Adamska, Aleksandra and Seger, Alexandra and Yasui, Hiroaki and van den Bos, Hilda and Radke, Katarzyna and Esfandyari, Javanshir and Bhave, Madhura Satish and Karlsson, Jenny and Spierings, Diana and Foijer, Floris and Gisselsson, David and Bexell, Daniel}},
  issn         = {{2375-2548}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{43}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Advances}},
  title        = {{Clinically relevant treatment of PDX models reveals patterns of neuroblastoma chemoresistance}},
  url          = {{http://dx.doi.org/10.1126/sciadv.abq4617}},
  doi          = {{10.1126/sciadv.abq4617}},
  volume       = {{8}},
  year         = {{2022}},
}