Abstract PR12: Identifying different functional mechanisms of invasion from mesenchymal and proneural subtypes of glioblastoma

Abstract

Abstract Glioblastoma multiforme (GBM) is the most frequent, aggressive and invasive type of primary brain tumors. Clinical management of patients with GBMs is confounded by the tumor cells' tendency to migrate and invade into adjacent brain. Understanding and targeting these invasive/dispersive malignant cells would address an unmet clinical need, and have a significant impact on patient quality of life and survival. The purpose of this study is to identify expression changes associated with distinct GBM subtypes that differentiate stationary core and invasive rim tumor cells. We used GBM invasion gene expression data (GSE12689), which consists of microdissected paired core v rim sets from 19 patient samples (Hoelzinger DB, et al Neoplasia. 2005. PMID: 1490313). Gene expression data on the 19 core samples were analyzed to determine specific GBM subtypes using the mesenchymal (MES) and proneural (PN) gene expression signatures (Verhaak RG et al Cancer Cell. 2010. PMID: 2818769.) resulting in 6 instances of MES, 7 PN, 3 uncertain-MES and 3 other. After subtype analysis, differentially expressed genes (DEGs) were identified between core and rim for the Mes and PN groups. Using a p-value threshold 0.005 (or p < 0.01), 216 (468) DEGs (core vs. rim) were identified from the MES-subtype, and 497 (1,028) DEGs were identified from the PN-subtype. The larger number of DEGs in the PN subtype suggests a more substantial (greater) adaptation of transcriptional change is necessary to transition to a invasive phenotype. The smaller number of changes in the MES samples suggests that cells of this form of GBM have an inherent migratory phenotype. Curiously, there was little gene overlap between MES and PN DEGs. A knowledge mining analysis was done to characterize biological concepts represented by the DEGs in each molecular subtype. The PN rim signature was enriched for genes involved in neuronal processes associated with synapse development and function. The PN core signature displayed genes associated with cell cycle progression. The MES core and rim signature represented a less homogeneous functional grouping of genes. There was a grouping of genes associated with vesicle movement, such as ARF1 and ARF3, associated with the MES rim. One gene of importance noted in the MES rim was autotaxin, which we have previously shown to be important in GBM invasion (Hoelzinger DB, et al. J Neurooncol. 2008 PMID: 17928955). No significant enriched biological concepts were evident in the MES core, however, individual genes of interest in the core such as the insulin receptor, BDNF and sonic hedgehog (SHH) were observed. Lastly, the ligand DLL4 and notch receptor (NOTCH1) are present, suggesting Notch signaling in the MES core. In summary, we analyzed a unique clinical GBM gene expression resource to identify patterns of differentially expressed genes associated with the invasive rim of MES and PN GBM samples. Molecular subtyping of the tumor has a marked influence on the changes in gene expression coincident to invasion. Disparity in the changes in patterns of differential gene expression between MES and PN GBM argues for wide-ranging adaptations necessary to affect dispersion in the brain, including tumor:microenvironment interactions, tumor cell adoption of a invasive phenoptype, and likely proliferative-, survival- and developmental-related changes. Such wide-ranging accommodation to succeed in invasion based on molecular subtyping raises opportunities by which to assess what the points of vulnerability may be in these malignant cells while they navigate through the brain to set up distant sites of tumor growth. (Supported by NIH CA U01CA168397) This abstract is also presented as Poster B92. Citation Format: Sungwon Jung, Seungchan Kim, Jeff Kiefer, Michael E. Berens. Identifying different functional mechanisms of invasion from mesenchymal and proneural subtypes of glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr PR12.