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RESEARCH PRODUCT
Patient-Derived Xenograft Models Reveal Intratumor Heterogeneity and Temporal Stability in Neuroblastoma.
Ingrid ØRaAna P. BerbegallDavid GisselssonJavanshir EsfandyariJenny KarlssonFredrik LevanderAnna BörjessonKristoffer Von StedingkKristoffer Von StedingkRosa NogueraKarin HanssonAngela Martinez-monleonTorbjörn BackmanSiv BeckmanDavid LindgrenJan KosterDaniel BexellHåkan AxelsonJakob WillforssSven PåhlmanNoémie BraekeveldtSusanne FranssonTommy Martinssonsubject
0301 basic medicineMaleProteomicsCancer ResearchGenotypeBiologyProteomicsPolymorphism Single NucleotideTranscriptomeTranslational Research Biomedical03 medical and health sciencesMiceNeuroblastoma0302 clinical medicineIntratumor heterogeneityNeuroblastomamedicineBiomarkers TumorAnimalsHumansIn patientTumor xenograftNeoplasm StagingGene Expression ProfilingInfantmedicine.diseasePhenotypeGene expression profilingDisease Models Animal030104 developmental biologyOncology030220 oncology & carcinogenesisCancer researchFemaleTranscriptomeNeoplasm Transplantationdescription
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 under-explored. 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. Significance: These findings underpin the complexity of PDX modeling as a means to advance translational applications against neuroblastoma. (C) 2018 AACR.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-01-01 | Cancer research |