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Page 69
CANCER STEM CELLS AND
ONCOLOGY RESEARCH
11th International Conference on
Journal of Medical Oncology and Therapeutics | Volume 3
Seamus Caragher et al., J Med Oncl Ther 2018, Volume 3
ACTIVATION OF DOPAMINE RECEPTOR
2 INCREASES TUMORGENECITY
AND ALTERS METABOLISM IN
GLIOBLASTOMA IN SUB-TYPE
DEPENDENT MANNER
Seamus Caragher, Jack Shireman, Cheol Hong Park, Mei
Huang, Jason Miska, Herbert Meltzer, Maijic Lesniak and
Atique Ahmed
Northwestern University, USA
O f all cancers, glioblastoma (GBM) remains one of the least treatable.
Evidence indicates cellular plasticity—GBM cells’ ability to adopt
various expression profiles and functional attributes—is a key factor in this
aggressive phenotype. This process includes the ability of differentiated
GBM cells to attain a glioma-intiating cell (GIC) phenotype, characterized
by heightened therapy-resistance and elevated self-renewal capacity. A
variety of factors in the microenvironment have been shown to influence
this process, including hypoxia, acidity, and therapeutic stress. Therefore,
a better understanding of the mechanisms governing this conversion
is needed. Developmental neurobiology suggests that dopamine, a
monoamine neurotransmitter, may represent one such factor. Dopamine
signaling influences differentiation of brain progenitor cells, highly similar
to GICs. We set out to investigate how dopamine influences cellular
plasticity in GBM. First, we analyzed epigenetic regulation of the five
dopamine receptors (DRDs) in patient derived xenograft (PDX) cells. We
found that therapy induces increased acetylation of H3K27 in the DRD2
promoter. Western blots and FACS confirmed increased DRD2 protein.
Next, we performed neurosphere assays in the presence of a specific
DRD2 agonist. Agonist treated classical PDX cells increased in sphere-
forming capacity, while proneural PDX showed no change. Blocking DRD2
attenuated neurosphere-formation. To determine what pathways drive
this DRD2 activated plasticity, we performed bioinformatics analysis
of human GBM samples. DRD2 expression correlated positively with
hypoxia inducible factor (HIF) signaling. Agonist treatment of PDX cells
induced HIF protein, despite normoxic conditions. Microarray analysis of
HIF genes confirmed subtype-dependent alterations in gene expression
following DRD2 activation. Finally, we examined how these gene
expression changes influence metabolism, a key functional output of
HIF signaling. Seahorse analysis revealed classical GBM cells augment
glycolytic rate following DRD2 activation, while proneural GBM cells
decrease their consumption of glucose. In summary, these data highlight
the contribution of CNS-specific molecules to cellular plasticity of GBM
Seamus Caragher earned his B.S. in Neurobiolo-
gy, summa cum laude and Phi Beta Kappa, from
Georgetown University in 2016. He then worked
in the laboratory of Atique Ahmed, PhD at the
Lurie Cancer Center of Northwestern University,
focusing on cellular plasticity and the influence
of the brain microenvironment in glioblastoma.
He is currently pursuing an MSc in Cancer Sci-
ences at the University of Glasgow as a British
Marshall Scholar.
BIOGRAPHY
cells and provide evidence for functional
differences in genetically defined tumor
subpopulations.