Patient-Derived Xenograft Models Reveal Intratumor Heterogeneity and Temporal Stability in Neuroblastoma

Cancer Research
Noémie BraekeveldtDaniel Bexell

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 pr...Continue Reading

Citations

Sep 4, 2019·International Journal of Cancer. Journal International Du Cancer·Jiahao ShiXianqun Fan
Mar 18, 2020·International Journal of Molecular Sciences·Sara Guerrero-AspizuaMarcela Del Río
Feb 5, 2019·Oncotarget·Kristoffer von StedingkDaniel Bexell
Sep 25, 2020·Science Translational Medicine·Karin HanssonDaniel Bexell
Sep 16, 2020·Cancer Metastasis Reviews·Michael W LeeAnna Capasso
Feb 15, 2019·Frontiers in Molecular Neuroscience·John Inge JohnsenMalin Wickström
Oct 31, 2021·Cancer Metastasis Reviews·Esteban Javier Rozen, Jason Matthew Shohet

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