Abstract 1886: mGluR1 drives invasion of proneural subtype of glioblastoma cells

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Abstract A major cause for the therapeutic failure and subsequent morbidity and mortality of glioblastoma (GBM) is the aggressive invasion of malignant cells into the surrounding normal brain that effectively renders complete surgical resection impossible and virtually assures recurrent tumor growth. Multi-omic profiling of GBM led to their molecular sub-classification into two distinct molecular subtypes: proneural (PN) and mesenchymal (MES). However, very little is known about shared or distinct invasion processes of cells in these genomically different subtypes. Using Microarray gene expression profiles of microdissected paired stationary core and invasive rim samples from 19 patients, we demonstrated that invasive gene signature of MES subtypes differs from PN. Specifically, using three orthogonal but intersecting bioinformatic approaches, i.e. gene set variation analysis, causal network analysis, and iRegulon analysis; we discovered that genes differentially expressed between PN core and rim could, to a meaningful degree, be accounted for based on their annotation as “regulated by the transcription factor REST”. REST functions as a repressor of gene expression. Of the genes repressed by REST, mGluR1 (Metabotropic Glutamate Receptor 1) was significantly overexpressed at the rim of PN glioma cells as compared to the core. Finally, we also investigated the role of mGluR1 in glutamate induced glioma cell migration; our results show that glutamate stimulates migration of proneural-like glioma cells (A172) as compare to non-proneural-like glioma cell (T98G). mGluR1 activation by glutamate has shown to induce activation of Pyk2 and Src in astrocytes; knockout of mGluR1 is not embryonic lethal. In summary, our data demonstrate that glutamate-induced glioma cell migration of PN subtype of GBM is dependent on mGluR1 and thus raises the prospect that therapeutic targeting of mGluR1 may be a novel approach to controlling the invasion of this deadly disease. Citation Format: Alena Gladwin, Sen Peng, Jeff Kiefer, Seugchan Kim, Michael Berens, Harshil D. Dhruv. mGluR1 drives invasion of proneural subtype of glioblastoma cells [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 1886. doi:10.1158/1538-7445.AM2017-1886