Comparative analyses of gene copy number and mRNA expression in glioblastoma multiforme tumors and xenografts

Abstract

Development of model systems that recapitulate the molecular heterogeneity observed among glioblastoma multiforme (GBM) tumors will expedite the testing of targeted molecular therapeutic strategies for GBM treatment. In this study, we profiled DNA copy number and mRNA expression in 21 independent GBM tumor lines maintained as subcutaneous xenografts (GBMX), and compared GBMX molecular signatures to those observed in GBM clinical specimens derived from the Cancer Genome Atlas (TCGA). The predominant copy number signature in both tumor groups was defined by chromosome-7 gain/chromosome-10 loss, a poor-prognosis genetic signature. We also observed, at frequencies similar to that detected in TCGA GBM tumors, genomic amplification and overexpression of known GBM oncogenes, such as EGFR, MDM2, CDK6, and MYCN, and novel genes, including NUP107, SLC35E3, MMP1, MMP13, and DDX1. The transcriptional signature of GBMX tumors, which was stable over multiple subcutaneous passages, was defined by overexpression of genes involved in M phase, DNA replication, and chromosome organization (MRC) and was highly similar to the poor-prognosis mitosis and cell-cycle module (MCM) in GBM. Assessment of gene expression in TCGA-derived GBMs revealed overexpression of MRC cancer genes AURKB, BIRC5, CCNB1, CCNB2, CDC2, CDK2, and FOXM1, which form a transcriptional network important for G2/M progression and/or checkpoint activation. Our study supports propagation of GBM tumors as subcutaneous xenografts as a useful approach for sustaining key molecular characteristics of patient tumors, and highlights therapeutic opportunities conferred by this GBMX tumor panel for testing targeted therapeutic strategies for GBM treatment.

Yes-Associated Protein 1 Exhibits Oncogenic Property in Gastric Cancer and Its Nuclear Accumulation Associates with Poor Prognosis

“…Amplification of this region, although infrequent, has been implicated in various human cancers (24)(25)(26)(27)(28)(29). Our array CGH (comparative genomic hybridization) analysis revealed amplification of YAP1 in 1 of 9 gastric cancer cell lines only (NCI-N87; Supplementary Fig.…”

Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion

“…Tumor cells were cultured as tumorspheres, using neural stem cell conditions including non-adherent growth and minimal essential media, to promote retention of tumor generating cells (40,41). The four human lines were selected based on their diversity of molecular and transcriptional properties, including EGFR amplification and EGFRvIII expression in GBM6, PDGFRA amplification in GBM5, and CDKN2C/p18(INK4c) homozygous deletion in GBM43 (35,36,42). Nanostring analysis of tumorsphere mRNA confirmed differences between the lines, including EGFR and EGFRvIII expression in GBM6, low expression of NF1 in GBM43, and robust expression of PDGFRA in all four lines (Supplemental Table 3).…”

“…GBM43, GBM6, and GBM5 are tumorsphere cultures of patient-derived xenografts (PDX). PDX were established as previously described (34,35) and have been genetically and transcriptionally profiled (1,35,36). GBM1 (SF9487) is a newly generated primary patient-derived tumorsphere culture from UCSF and when injected into the striatum of nude mice generates highly invasive GBM (Supplemental Figure 1, Supplemental Table 1, and Supplemental Material and Methods).…”

Epidermal growth factor induces matrix metalloproteinase-1 (MMP-1) expression and invasion in glioma cell lines via the MAPK pathway

“…We have reported that there is a significant increase in MMP-1 mRNA levels in tumor samples from patients with GBM relative to normal brain [13]. MMP-1, which is not typically expressed in normal brain, has been shown to be elevated in gliomas [22] and correlates with tumor grade and survival time [12].…”