PhD Public Seminar - Matthaeus Ware
PhD Public Seminar - Matthaeus Ware
Date: Friday, July 12th, 2024
Time: 2:00–3:00 PM EST
Location: Multimedia Room, 3rd floor, PGCRL (686 Bay Street)
Or via Zoom:
Meeting URL: https://utoronto.zoom.us/j/86503964661
Meeting ID: 865 0396 4661
Meeting Passcode: PHD
The influence of dopaminergic activity on glioblastoma initiation and progression.
Abstract:
Glioblastoma (GBM) is an incurable disease and the deadliest form of central nervous system (CNS) malignancy. Despite major advances in our understanding of GBM biology in recent years, the prognosis for patients who develop this disease has hardly improved. If we hope to find new treatments for GBM that are safe and effective, we desperately need to reform our thinking and examine historically overlooked contributions to tumour development, including interactions with the nervous system. The brain’s chemical milieu is rich with neurotransmitters, and a screen of 680 neuroactive compounds on patient-derived GBM stem cells in vitro strongly implicated the dopaminergic pathway as a critical regulator of the GBM niche. Dopamine signalling is essential for reward learning, movement, and cognition, and its dysregulation is linked to a diversity of brain diseases including drug addiction to Parkinson’s.
Through my PhD research, I aimed to determine how the brain’s dopamine signalling affects GBM development. I hypothesized that GBM cells arising/residing in dopamine projection zones exploit dopaminergic activity for tumour growth. To address this hypothesis, I developed in vivo systems to study GBM niches in the context of either controlled activation or depletion of DAergic inputs. I executed these targeted manipulations of dopaminergic neurons using optogenetic stimulation, genetics-induced depletion, and neurotoxin-mediated ablation in mice. Then, I overlaid the dopaminergic manipulations onto two mouse models of GBM—genetic and patient-derived xenograft models—to study tumour initiation and progression, respectively, in the context of these changes. My results show that GBM-like tumours do not form in the striatum when dopaminergic innervations are removed from that brain region. Strikingly, this effect is reversed when L-DOPA, the immediate precursor of dopamine that partially rescues dopamine levels in the striatum, is administered to the mice. Together, these results suggest that dopamine is both necessary and sufficient to enable the development of striatal tumours.
The work I will present in this thesis begins to unravel the dopaminergic influence on GBM and invites further experiments to dissect the mechanism behind these phenomena. This research may provide a biological basis for redeploying existing treatments—that modulate dopamine signalling and are well-tolerated for CNS disorders—to patients with this deadly brain cancer.