Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor. Currently, treatment for GBM involves surgical resection, chemotherapy, and radiation, resulting in a median survival of 15 months. This poor outcome highlights the need for improved therapeutic approaches to treat GBM patients. The signal transducer and activator of transcription 3 (STAT3) pathway is abnormally active in GBM, primarily in the mesenchymal subtype of GBM. STAT3 regulates various cellular processes including: proliferation, invasion and resistance to therapy. The Weiss lab has established a large collection of brain tumor initiating cell (BTIC) lines derived from GBM patients. These GBM BTIC lines are used to model the subpopulation of cells that are predicted to be the source of resistance and recurrence following treatment. Here, we are focused on the role of STAT3 as a central regulator of proliferation, invasion and metabolism in GBM BTIC lines. We show that activation of the STAT3 pathway using the ligand oncostatin M (OSM) or by stably expressing a constitutively active STAT3 mutant (STAT3C) in GBM BTIC lines leads to an increase in proliferation. STAT3 is known to regulate the expression of multiple matrix metalloproteinases (MMPs) that promote invasion. Using time-lapse imaging of 3D sphere invasion into matrigel, we observed that JAK2 (an activator of STAT3) and direct STAT3 inhibitors decrease invasion of GBM BTICs. Our analysis of gene expression data available from The Cancer Genome Atlas (TCGA) demonstrates that a glutamine metabolism gene expression signature correlates inversely with a STAT3 gene expression signature in GBM patient samples. Conversely, similar analysis reveals that a high glycolysis gene expression signature correlates with a high STAT3 gene expression signature. We hypothesize that targeting the STAT3 pathway will decrease proliferation and invasion while simultaneously sensitizing GBM BTIC lines to inhibition of glutamine metabolism. Glutaminase (GLS) is the first enzyme to act on glutamine, converting glutamine to glutamate, which is then further processed to α-ketoglutarate (αKG). αKG is important for the production of biosynthetic macromolecules that are essential for cell growth. Chemical inhibition of GLS decreases cell growth in culture with varying levels of sensitivity across multiple GBM BTIC lines. Interestingly, activation of the STAT3 pathway using OSM de-sensitizes GBM BTIC lines to GLS inhibition. Furthermore, chemical inhibition of JAK2 sensitizes a subset of GBM BTIC lines to GLS inhibition resulting in a further decrease in cell growth. Overall, we show that STAT3 is a central hub in GBM BTIC lines that modulates proliferation, invasion, and sensitivity to GLS inhibition. Currently, we are continuing these studies in vivo using GBM BTIC orthotopic xenografts in mice.
Citation Format: Ian Restall, H. Artee Luchman, Samuel Weiss. STAT3 is a central regulator of proliferation, invasion and metabolism in GBM tumor initiating cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2521.