Date of Award
Spring 4-1-2024
Document Type
Thesis (Ph.D.)
Department or Program
Molecular and Systems Biology
First Advisor
Matthew Havrda
Abstract
Primitive stem cell-like populations that are prone to malignant transformation reside in the brain throughout adulthood. My lab’s reports and many others have characterized subsets of glioma cells reminiscent of adult stem-like cells implicating them rational candidates for cell-targeted therapies. Emerging evidence suggests that the neurotransmitter microenvironment influences these stem-like cells during glioma progression providing an inroad to study neuromodulators in glioma. Some glioma stemlike cells share characteristics with adult tissue oligodendrocyte progenitor cells. Primitive cells of the oligodendroglial lineage express muscarinic acetylcholine receptors (mAChRs), and their “stemness” is maintained by the acetylcholine (ACh) neurotransmitter. Here, I conduct transcriptomic, electrophysiological, biochemical, an in vivo studies to characterize muscarinic acetylcholine receptor expression and function in glioma. Studies evaluate human glioma single nuclei transcriptomic data, murine oligodendroglial progenitor cell-like glioma cell cultures and examine an FDA-approved antimuscarinic drug in vitro and in patient-derived glioma grafts in mice. CHRM3 muscarinic acetylcholine receptor is highly expressed in the proneural subset of glioma cells. Murine oligodendroglial progenitor cell-like glioma cell cultures are electrochemically responsive to acetylcholine. Treatment with the anti-muscarinic benztropine suppressed calcium signaling and proliferation in cultured glioma OPC-like cells. In vivo, pretreatment of established tumors in mice with benztropine blocked host-to-host transfer of patient derived glioma grafts. Data indicate that cholinergic signaling pathways are functional in glioma stem-like cells and that modulation of muscarinic receptors can influence glioma progression. My results provide a platform for repositioning readily available brain permeant small molecule modifiers of the cholinergic system for the treatment of glioma.
Recommended Citation
Anand, Sumyuktha Vijay, "Targeting Cholinergic Signaling in Glioblastoma" (2024). Dartmouth College Ph.D Dissertations. 253.
https://digitalcommons.dartmouth.edu/dissertations/253