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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Susanne Fransson
  • Angela Martinez-Monleon
  • Karin Hansson
  • Torbjörn Backman
  • Siv Beckman
  • Javanshir Esfandyari
  • Ana P. Berbegall
  • Rosa Noguera
  • Jan Koster
  • Tommy Martinsson
Organisations
External organisations
  • Academic Medical Center
  • University of Amsterdam
  • Skåne University Hospital
  • University of Gothenburg
  • University of Valencia
  • CIBERONC Centro de Investigación Biomédica en Red Cáncer
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)5958-5969
Number of pages12
JournalCancer Research
Volume78
Issue number20
Publication statusPublished - 2018
Publication categoryResearch
Peer-reviewedYes