Abstract 1937: Evolution of neuroblastoma patient-derived orthotopic xenografts through space and time

Abstract

Abstract Background Recently, we established orthotopic neuroblastoma patient-derived xenografts (PDXs) which maintain the phenotypic, genomic, and stromal hallmarks of patient tumors. Here we examined how PDXs evolve following years of in vivo growth. Materials and Methods We established up to eight in vivo generations of neuroblastoma orthotopic PDXs through serial passaging in NSG mice. RNA sequencing, exome sequencing and SNP array analysis were used to analyze patient tumors and PDXs from different in vivo generations. Results Using SNP analysis, we found mostly a remarkable genomic stability at chromosomal level between patient tumors, early and late PDX generations. RNA-seq revealed that patient tumors expressed higher levels of genes involved in immune responses and ECM metabolism compared to PDXs. Different PDX samples clustered correctly into their respective tumor type. PDXs from all early generations did not separate from PDXs from late generations. Thus, gene expression levels are surprisingly often quite stable despite years of in vivo growth. To shed light on neuroblastoma intratumor heterogeneity, we implanted 10 different tumor fragments from a single patient tumor into mice. We classified the 10 mice into three groups based on the time periods required for tumor growth. RNA-seq showed that each of these groups had a distinct gene expression profile and pathways involved in neuroblastoma progression have been identified. Conclusions Neuroblastoma orthotopic PDXs are often very stable at chromosomal and gene expression levels despite years of in vivo growth. We utilized multiple PDXs to show functional intratumor heterogeneity coupled to distinct gene expression profile. Citation Format: Noémie Braekeveldt, Susanne Fransson, Kristoffer von Stedingk, Ingrid Öra, Rosa Noguera, Tommy Martinsson, David Gisselsson Nord, Sven Påhlman, Daniel Bexell. Evolution of neuroblastoma patient-derived orthotopic xenografts through space and time [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1937. doi:10.1158/1538-7445.AM2017-1937