@article {Caragher454389, author = {Seamus P. Caragher and Jack M. Shireman and Mei Huang and Jason Miska and Shivani Baisiwala and Cheol Hong Park and Miranda R. Saathoff and Louisa Warnke and Ting Xiao and Maciej S. Lesniak and C. David James and Herbert Meltzer and Andrew K. Tryba and Atique U Ahmed}, title = {Activation of dopamine receptor 2 (DRD2) prompts transcriptomic and metabolic plasticity in glioblastoma}, elocation-id = {454389}, year = {2018}, doi = {10.1101/454389}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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, in both sexes of humans and mice, 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. 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, we show that dopamine can alter the metabolic behavior of GBM cells, increasing glycolysis. Finally, we show 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.This work was supported by the National Institute of Neurological Disorders and Stroke grant 1R01NS096376, the American Cancer Society grant RSG-16-034-01-DDC (to A.U.A.) and National Cancer Institute grant R35CA197725 (to M.S.L) and P50CA221747 SPORE for Translational Approaches to Brain Cancer. We would like to thank Meijing Wu for the statistical analysis for the preparation of this manuscript.}, URL = {https://www.biorxiv.org/content/early/2018/11/16/454389}, eprint = {https://www.biorxiv.org/content/early/2018/11/16/454389.full.pdf}, journal = {bioRxiv} }