Clinically relevant treatment of PDX models reveals patterns of neuroblastoma chemoresistance
(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
(Less)
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.
- author
- organization
- publishing date
- 2022-10-28
- 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
-
- scopus:85141003573
- pmid:36306349
- 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
- 2024-09-20 18:14:02
@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}}, }