Abstract 4222: Targeting HMGA2 suppresses GBM stemness, invasion and tumorigenicity

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) thought to be critical for 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. We found increased HMGA2 expression in a subset of primary human GBM tumors, in multiple patient-derived GBM neurosphere and adherent cell lines, and in the mesenchymal subgroup of GBM in The Cancer Genome Atlas (TCGA) database. Lentiviral short hairpin RNA (shRNA)-lowered HMGA2 protein levels and significantly reduced invasion and clonogenicity of GBM cell lines in transwell invasion and soft agar colony formation assays. Pharmacological inhibition of HMGA proteins using the DNA minor-groove binding drug Netropsin significantly inhibited growth of the U-87 MG GBM cell line (P<0.01) in MTS assays. Mice bearing orthotopic GBM neurosphere xenograft lines transduced with HMGA2 shRNA lived longer (median survival = 108 days) compared to control shRNA (median survival = 67.5 days) (P<0.0001 by log-rank analysis). Conversely, lentiviral-mediated overexpression of HMGA2 in GBM cell lines increased invasion, clonogenicity and resistance to radiation in vitro (P<0.01). Overexpression of HMGA2 also promoted GBM tumor formation in vivo in orthotopic xenografts. To elucidate the molecular mechanism by which HMGA2 promotes invasion and stemness in GBM, we performed mRNA expression profiling on GBM neurosphere lines lentivirally transduced to express HMGA2 or empty vector control. We found increased CD44 expression in HMGA2-overexpressing GBM neurosphere lines compared to control, and confirmed this result by western blotting. Together, our results suggest an oncogenic role of HMGA2 in promoting GBM tumorigenicity by increasing invasiveness and a stem cell-like state, and show that HMGA2 is a potential therapeutic target in GBM. Citation Format: Harpreet Kaur, Marianne Hütt-Cabezas, Isabella Taylor, Laura Asnaghi, Fausto Rodriguez, Brent A. Orr, Charles G. Eberhart, Eric H. Raabe. Targeting HMGA2 suppresses GBM stemness, invasion and tumorigenicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4222. doi:10.1158/1538-7445.AM2015-4222