Abstract 4192: Global gene expression profiling confirms the molecular fidelity of primary tumor-based orthotopic xenograft mouse models of medulloblastoma

Abstract

Abstract Clinically relevant animal models are needed for understanding biology and testing novel therapies in medulloblastoma (MB), the most common malignant brain tumor that occurs in children. We have recently established a panel of orthotopic xenograft mouse models of MB through direct injection of fresh surgical specimens into the cerebella of Rag2/SCID mice. The xenograft tumors were previously shown to have replicated key histopathological phenotypes and invasive growth characteristics of the original patient tumors. The objective of the current study is to complete the molecular characterization of 11 MB models that have been serially passaged in vivo in mouse brains for at least three generations. Whole genome gene expression profiling was performed in duplicate with Illumina HumanWG6 v3 gene expression profiling beadchip that contains more than 48,000 probes. Our results showed that the xenograft tumors are molecularly accurate. When the nine passage I xenograft tumors were compared with their original patient tumors, high correlation coefficiency were observed (r2 >0.95 in five models, >0.9 in three models, and >0.85 in one model). Serial subtransplantation up to five times did not cause significant changes of gene expression pattern (r2>0.9 in eight models, >0.8 in three models). Using RNAs from 4 normal fetal brains, one child cerebellum, and 5 adult cerebella as control, we further showed that these xenograft models, although molecularly independent displaying distinct gene expression profiles, can be classified into five different subcategories. A selected set of the differentially expressed genes were validated using real-time RT-PCR and Immunohistochemistry. In conclusion, this study provided strong experimental evidence to demonstrate that primary tumor-based orthotopic xenograft mouse models of MBs are molecularly accurate, and our findings of genetic abnormalities should significantly facilitate the rationally designed preclinical drug screenings in the near future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4192.