Patient-derived xenograft models reveal intratumor heterogeneity and temporal stability in neuroblastoma
Menée à l'aide de xénogreffes dérivées de tumeurs de patients atteints d'un neuroblastome, cette étude met notamment en évidence une hétérogénéité génétique intratumorale et, à l'aide de 10 xénogreffes dérivées d'un unique patient, la stabilité temporelle de cette hétérogénéité
Patient-derived xenografts (PDXs) 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 two years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of neuroblastoma patients. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phospho-proteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in high-risk neuroblastoma patients. 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.
Cancer Research , article en libre accès, 2017