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

Noémie Braekeveldt, Kristoffer Von Stedingk, Susanne Fransson, Angela Martinez-Monleon, David Lindgren, Håkan Axelson, Fredrik Levander, Jakob Willforss, Karin Hansson, Ingrid Øra, Torbjörn Backman, Anna Börjesson, Siv Beckman, Javanshir Esfandyari, Ana P. Berbegall, Rosa Noguera, Jenny Karlsson, Jan Koster, Tommy Martinsson, David GisselssonSven Påhlman, Daniel Bexell

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

21 Citeringar (SciVal)

Sammanfattning

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.

Originalspråkengelska
Sidor (från-till)5958-5969
Antal sidor12
TidskriftCancer Research
Volym78
Utgåva20
DOI
StatusPublished - 2018

Ämnesklassifikation (UKÄ)

  • Cancer och onkologi

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