Activation of dopamine receptor 2 prompts transcriptomic and metabolic plasticity in glioblastoma

Seamus P. Caragher, Jack M. Shireman, Mei Huang, Jason Miska, Fatemeh Atashi, Shivani Baisiwala, Cheol Hong Park, Miranda R. Saathoff, Louisa Warnke, Ting Xiao, Maciej S. Lesniak, C. David James, Herbert Meltzer, Andrew K. Tryba, Atique U. Ahmed*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

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 dopamine receptor 2 (DRD2), with elevated expression in the glioma-initiating cell (GIC) population. Stimulation of DRD2 caused a neuron-like hyperpolarization 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.

Original languageEnglish (US)
Pages (from-to)1982-1993
Number of pages12
JournalJournal of Neuroscience
Volume39
Issue number11
DOIs
StatePublished - Mar 13 2019

Keywords

  • Cancer stem cell
  • Cellular plasticity
  • Dopamine
  • Glioblastoma

ASJC Scopus subject areas

  • Neuroscience(all)

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