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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Susanne Fransson
  • Angela Martinez-Monleon
  • Karin Hansson
  • Torbjörn Backman
  • Siv Beckman
  • Javanshir Esfandyari
  • Ana P. Berbegall
  • Rosa Noguera
  • Jan Koster
  • Tommy Martinsson
Enheter & grupper
Externa organisationer
  • Academic Medical Center
  • University of Amsterdam
  • Skåne University Hospital
  • University of Gothenburg
  • University of Valencia
  • CIBERONC Centro de Investigación Biomédica en Red Cáncer
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Sidor (från-till)5958-5969
Antal sidor12
TidskriftCancer Research
Volym78
Utgivningsnummer20
StatusPublished - 2018
PublikationskategoriForskning
Peer review utfördJa