J Neurosci. 2019 Jan 16. pii: 1589-18. doi: 10.1523/JNEUROSCI.1589-18.2018. [Epub ahead of print]

Caragher SP, Shireman JM, Huang M, Miska J, Atashi F, Baisiwala S, Hong Park C, Saathoff MR, Warnke L, Xiao T, Lesniak MS, James CD, Meltzer H1, Tryba AK2, Ahmed AU.

 

Author information:

1. Department of Psychiatry, Feinberg School of Medicine, Northwestern University, Chicago, IL USA 60616.

2. Department of Pediatrics, Pritzker School of Medicine, University of Chicago, Chicago, IL USA 60637.

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, 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.

 

Copyright © 2019 the authors.