TY - JOUR T1 - Activation of dopamine receptor 2 (DRD2) prompts transcriptomic and metabolic plasticity in glioblastoma JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.1589-18.2018 SP - 1589-18 AU - Seamus P. Caragher AU - Jack M. Shireman AU - Mei Huang AU - Jason Miska AU - Fatemeh Atashi AU - Shivani Baisiwala AU - Cheol Hong Park AU - Miranda R. Saathoff AU - Louisa Warnke AU - Ting Xiao AU - Maciej S. Lesniak AU - C. David James AU - Herbert Meltzer AU - Andrew K. Tryba AU - Atique U Ahmed Y1 - 2019/01/16 UR - http://www.jneurosci.org/content/early/2019/01/15/JNEUROSCI.1589-18.2018.abstract N2 - Glioblastoma (GBM) is one of the most aggressive and lethal tumor types. Evidence continues to accrue indicating that the complex relationship between GBM and the brain microenvironment contributes to this malignant phenotype. However, the interaction between GBM and neurotransmitters, signaling molecules involved in neuronal communication, remains incompletely understood. Here we examined, using human patient derived xenograft lines, how the monoamine dopamine influences GBM cells. We demonstrate that GBM cells express DRD2, with elevated expression in the glioma-initiating cell (GIC) population. Stimulation of DRD2 caused neuron-like depolarization exclusively in GICs. In addition, long-term activation of DRD2 heightened the sphere-forming capacity of GBM cells, as well as tumor engraftment efficiency in both male and female mice. Mechanistic investigation revealed that DRD2 signaling activates the hypoxia response and functionally alters metabolism. Finally, we found that GBM cells synthesize and secrete dopamine themselves, suggesting a potential autocrine mechanism. These results identify dopamine signaling as a potential therapeutic target in GBM and further highlight neurotransmitters as a key feature of the pro-tumor microenvironment.Significance Statement:This work offers critical insight into the role of the neurotransmitter dopamine in the progression of GBM. We show that dopamine induces specific changes in the state of tumor cells, augmenting their growth and shifting them to a more stem-cell like state. Further, our data illustrate that dopamine can alter the metabolic behavior of GBM cells, increasing glycolysis. Finally, this work demonstrates that GBM cells, including tumor samples from patients, can synthesize and secrete dopamine, suggesting an autocrine signaling process underlying these results. These results describe a novel connection between neurotransmitters and brain cancer, further highlighting the critical influence of the brain milieu on GBM. ER -