Abstract 3742: Targeting the stem cell factor HMGA2 to improve outcomes in glioblastoma.

Abstract

Abstract Glioblastoma Multiforme (GBM) causes the majority of brain tumor-related deaths in the United States. The high invasiveness of GBM prevents complete surgical resection, allowing tumor recurrence. The lack of curative treatment highlights a dire need to develop specific targeted therapeutics. Identifying and targeting novel molecular markers in glioma stem-like cells (GSCs), one of the major causes of tumor invasion and recurrence, could lead to development of better therapies. HMGA2, a non-histone transcriptional modulator, is a regulator of normal and cancer stem cells. The significance of HMGA2 as a potential therapeutic target in GBM has not been investigated. To elucidate the role of HMGA2 in GBM, we have used a combination of in vitro and in vivo techniques in the present study. We found high expression of HMGA2 mRNA and protein in a subset of primary brain tumor samples from GBM patients, GBM cell lines and GBM stem-cell lines using quantitative real-time PCR and immunoblotting. Short hairpin RNA (shRNA)-mediated reduction of HMGA2 significantly inhibited invasion of GBM cell lines (U-87 MG and LN-229, 32 and 70% inhibition, respectively, with HMGA2 shRNA vs. control shRNA, P<0.001) and GBM stem cell lines (040821, 62% inhibition with HMGA2 shRNA vs. control shRNA, P<0.001) through Matrigel in vitro by transwell invasion assays. Conversely, overexpression of HMGA2 in GBM stem cell lines increased invasion (130% increase with HMGA2 overexpression vs. control vector, P<0.0001) through Matrigel in vitro as demonstrated by transwell invasion assays. In addition, overexpression of HMGA2 increased clonogenicity of GBM stem cell lines in vitro in soft agar and methylcellulose clonogenic assays (40% increase with HMGA2 overexpression vs. control vector, P<0.0001). Importantly, Kaplan-Meier analysis showed increased survival of mice injected with GBM stem cell lines transduced with HMGA2 shRNA compared to control shRNA (P<0.05) in an in vivo, orthotopic, intracranial mouse xenograft model. Together, our results suggest the importance of HMGA2 in promoting tumorigenicity of GBM by increasing invasiveness and a stem-like state, thereby suggesting that HMGA2 is a potential therapeutic target in GBM. Future studies are aimed at elucidating the molecular mechanism by which HMGA2 regulates invasion and stemness in GBM. Citation Format: Harpreet Kaur, Marianne Hutt, Xing-gang Mao, Charles G. Eberhart, Eric H. Raabe. Targeting the stem cell factor HMGA2 to improve outcomes in glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3742. doi:10.1158/1538-7445.AM2013-3742