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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

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

Fingerprint

Dopamine Receptors
Glioblastoma
Dopamine
Neurotransmitter Agents
Tumor Microenvironment
Heterografts
Glioma
Neoplasms
Communication
Phenotype
Neurons
Brain
Population

Keywords

  • Cancer stem cell
  • Cellular plasticity
  • Dopamine
  • Glioblastoma

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Caragher, Seamus P. ; Shireman, Jack M. ; Huang, Mei ; Miska, Jason Michael ; Atashi, Fatemeh ; Baisiwala, Shivani ; Park, Cheol Hong ; Saathoff, Miranda R. ; Warnke, Louisa ; Xiao, Ting ; Lesniak, Maciej S ; James, Charles David ; Meltzer, Herbert Y ; Tryba, Andrew K. ; Ahmed, Atique Uddin. / Activation of dopamine receptor 2 prompts transcriptomic and metabolic plasticity in glioblastoma. In: Journal of Neuroscience. 2019 ; Vol. 39, No. 11. pp. 1982-1993.
@article{5d45fda4d4ab44e489f3ad662f0d9798,
title = "Activation of dopamine receptor 2 prompts transcriptomic and metabolic plasticity in glioblastoma",
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.",
keywords = "Cancer stem cell, Cellular plasticity, Dopamine, Glioblastoma",
author = "Caragher, {Seamus P.} and Shireman, {Jack M.} and Mei Huang and Miska, {Jason Michael} and Fatemeh Atashi and Shivani Baisiwala and Park, {Cheol Hong} and Saathoff, {Miranda R.} and Louisa Warnke and Ting Xiao and Lesniak, {Maciej S} and James, {Charles David} and Meltzer, {Herbert Y} and Tryba, {Andrew K.} and Ahmed, {Atique Uddin}",
year = "2019",
month = "3",
day = "13",
doi = "10.1523/JNEUROSCI.1589-18.2018",
language = "English (US)",
volume = "39",
pages = "1982--1993",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "11",

}

Activation of dopamine receptor 2 prompts transcriptomic and metabolic plasticity in glioblastoma. / Caragher, Seamus P.; Shireman, Jack M.; Huang, Mei; Miska, Jason Michael; Atashi, Fatemeh; Baisiwala, Shivani; Park, Cheol Hong; Saathoff, Miranda R.; Warnke, Louisa; Xiao, Ting; Lesniak, Maciej S; James, Charles David; Meltzer, Herbert Y; Tryba, Andrew K.; Ahmed, Atique Uddin.

In: Journal of Neuroscience, Vol. 39, No. 11, 13.03.2019, p. 1982-1993.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Activation of dopamine receptor 2 prompts transcriptomic and metabolic plasticity in glioblastoma

AU - Caragher, Seamus P.

AU - Shireman, Jack M.

AU - Huang, Mei

AU - Miska, Jason Michael

AU - Atashi, Fatemeh

AU - Baisiwala, Shivani

AU - Park, Cheol Hong

AU - Saathoff, Miranda R.

AU - Warnke, Louisa

AU - Xiao, Ting

AU - Lesniak, Maciej S

AU - James, Charles David

AU - Meltzer, Herbert Y

AU - Tryba, Andrew K.

AU - Ahmed, Atique Uddin

PY - 2019/3/13

Y1 - 2019/3/13

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 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.

AB - 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.

KW - Cancer stem cell

KW - Cellular plasticity

KW - Dopamine

KW - Glioblastoma

UR - http://www.scopus.com/inward/record.url?scp=85062875936&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062875936&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.1589-18.2018

DO - 10.1523/JNEUROSCI.1589-18.2018

M3 - Article

VL - 39

SP - 1982

EP - 1993

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 11

ER -