Patient-derived xenograft models reveal intratumor heterogeneity and temporal stability in neuroblastoma
(2018) In Cancer Research 78(20). p.5958-5969- Abstract
Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using... (More)
Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research.
(Less)
- author
- organization
-
- Molecular Pediatric Oncology (research group)
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- Childhood Cancer Research Unit (research group)
- Kidney cancer research group (research group)
- Department of Immunotechnology
- Pediatric surgery (research group)
- Paediatrics (Lund)
- Division of Translational Cancer Research
- Pathways of cancer cell evolution (research group)
- publishing date
- 2018
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cancer Research
- volume
- 78
- issue
- 20
- pages
- 12 pages
- publisher
- American Association for Cancer Research Inc.
- external identifiers
-
- pmid:30154149
- scopus:85054898690
- ISSN
- 0008-5472
- DOI
- 10.1158/0008-5472.CAN-18-0527
- language
- English
- LU publication?
- yes
- id
- 81a64098-f3b7-4e3e-8217-f361e1e694ed
- date added to LUP
- 2018-10-30 12:20:21
- date last changed
- 2024-09-18 05:34:39
@article{81a64098-f3b7-4e3e-8217-f361e1e694ed, abstract = {{<p>Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research.</p>}}, author = {{Braekeveldt, Noémie and Von Stedingk, Kristoffer and Fransson, Susanne and Martinez-Monleon, Angela and Lindgren, David and Axelson, Håkan and Levander, Fredrik and Willforss, Jakob and Hansson, Karin and Øra, Ingrid and Backman, Torbjörn and Börjesson, Anna and Beckman, Siv and Esfandyari, Javanshir and Berbegall, Ana P. and Noguera, Rosa and Karlsson, Jenny and Koster, Jan and Martinsson, Tommy and Gisselsson, David and Påhlman, Sven and Bexell, Daniel}}, issn = {{0008-5472}}, language = {{eng}}, number = {{20}}, pages = {{5958--5969}}, publisher = {{American Association for Cancer Research Inc.}}, series = {{Cancer Research}}, title = {{Patient-derived xenograft models reveal intratumor heterogeneity and temporal stability in neuroblastoma}}, url = {{http://dx.doi.org/10.1158/0008-5472.CAN-18-0527}}, doi = {{10.1158/0008-5472.CAN-18-0527}}, volume = {{78}}, year = {{2018}}, }