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Patient-derived xenograft models reveal intratumor heterogeneity and temporal stability in neuroblastoma

Braekeveldt, Noémie LU ; Von Stedingk, Kristoffer LU ; Fransson, Susanne; Martinez-Monleon, Angela; Lindgren, David LU ; Axelson, Håkan LU ; Levander, Fredrik LU ; Willforss, Jakob LU ; Hansson, Karin LU and Øra, Ingrid LU , et al. (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.

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Cancer Research
volume
78
issue
20
pages
12 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:85054898690
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-18-0527
language
English
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yes
id
81a64098-f3b7-4e3e-8217-f361e1e694ed
date added to LUP
2018-10-30 12:20:21
date last changed
2019-01-13 06:17:25
@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},
  volume       = {78},
  year         = {2018},
}