Joelle Martin's Dissertation Defense (5/11/2021): Modulation of System XC-Mediated Glutamate Release in Glioblastoma Multiforme Via the Extracellular Matrix
Dissertation Defense: Modulation of system xc- mediated glutamate release in glioblastoma multiforme via the extracellular matrix: the agony and the xCTasy
Joelle Martin
Graduate Student, Virginia Tech Translational Biology, Medicine, and Health
Graduate Research Assistant, Sontheimer Lab, Fralin Biomedical Research Institute at VTC
May 11, 2021 at 1:00 p.m.
About this Dissertation
Glioblastoma multiforme (GBM) is an advanced and aggressive form of brain cancer. Incidence of this disease in the United States of America is approximately 3.19 per 100,000 individuals, which translates to more than 13,000 expected annual diagnoses. These tumors arise from genetic mutations that instruct cells to replicate and migrate abnormally. Despite an aggressive medical armamentarium that includes maximal surgical resection, chemotherapy, and radiation, GBM patients have an expected survival period of 12-15 months after diagnosis. Previous studies have shown that approximately 50% of GBM patients have unusually high expression levels of the System xc- (SXC) protein. SXC is a protein transporter located at the membrane of GBM cells, and facilitates the exchange of the excitatory neurotransmitter glutamate for the amino acid dimer cystine. SXC exports glutamate out of the tumor cell, where it can then bind to glutamate receptors on surrounding neurons. In the brain, the concentration of extracellular glutamate must be tightly regulated to prevent hyperexcitability of neurons, which may lead to cell death and the induction of seizures. In patients whose tumors highly express SXC, studies have shown that glutamate levels can rise to concentrations over 100 times greater than the levels seen in normal brain tissue. Additionally, glutamate has been shown to stimulate GBM cells to migrate within the brain and establish secondary tumor sites. The medical and scientific community is justifiably interested in discovering novel methods for regulating or inhibiting SXC-mediated glutamate release. While SXC inhibitors have been identified, clinical studies have determined they are not appropriate for the clinical treatment of GBM. Thus the focus of this project was to identify novel molecular regulators of SXC. To that end, Martin, working in the Sontheimer Lab, explored two signaling molecules that are known to promote GBM pathogenesis: CD44 and the epidermal growth factor receptor (EGFR). Her research found no evidence to support a role for CD44 in regulating SXC in GBM. However, Martin was able to determine, through genetic and pharmacologic manipulation of patient-derived GBM cells, that EGFR regulates SXC expression and function. The results of these experiments confirmed EGFR as a key signaling protein involved in orchestrating SXC-mediated glutamate release, and may inform future clinical studies investigating combinatorial therapies for GBM patients.
More About the Candidate and Project
Education
Virginia Tech Translational Biology, Medicine, and Health, Ph.D. Candidate
Washington State University, B.S., Neuroscience
Training
Graduate Research Assistant, Sontheimer Lab, Fralin Biomedical Research Institute at VTC
Mentor
Harald Sontheimer, Ph.D., Adjunct Professor, Fralin Biomedical Research Institute at VTC
Committee Members
- Michelle Olsen, Ph.D., Associate Professor and Director of Graduate Studies, School of Neuroscience, College of Science, Virginia Tech
- Robert Gourdie, Ph.D., Professor, and Director, Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at VTC
- Jennifer Munson, Ph.D., Associate Professor, Fralin Biomedical Research Institute at VTC
Honors
Zeta Beta Tau Cancer Research Award, Fralin Biomedical Research Institute at VTC, 2020
Ray Gaskins Health Sciences Scholarship, Fralin Biomedical Research Institute at VTC, 2020
Travel Fund Program Award, Graduate School Assembly, Virginia Tech, 2020
Oral presentation award, 36th Annual Graduate Student Assembly Research Symposium, Blacksburg, Va., 2020
Graduate Research Development Program Award, Graduate School Assembly, Virginia Tech, 2019
Travel Fund Program Award, Graduate School Assembly, Virginia Tech, 2017
Service
Graduate Research Development Program Grant Reviewer, Virginia Tech, 2021
NeuroSurf Peer Mentor, Fralin Biomedical Research Institute at VTC, 2018-2019
Graduate Research Development Program Grant Reviewer, Virginia Tech, 2018
Judge for the 2018 Western Virginia Regional Science and Engineering Fair at Virginia Western Community College, 2018
Presentations
Oral
Identifying dynamic regulators of glutamate transport in glioblastoma multiforme. 36th Annual Graduate Student Assembly Research Symposium, Blacksburg, Va., 2020
Modulation of System xc- mediated glutamate release in glioblastoma multiforme. Eastern Virginia Medical School Graduate Student Research Conference. Norfolk, Va., 2020
Sheathing zystem xc-: the double-edged sword of glioblastoma. 35th Annual Graduate Student Assembly Research Symposium, Blacksburg, Va., 2019
GLIA: The unsung heroes of our brains. Roanoke Graduate Student Association Public Lecture Series, Roanoke, Va., 2018
Posters
EGFR as a dynamic regulator of system xc- mediated glutamate release in glioblastoma multiforme (Poster). Central Virginia Chapter of Society for Neuroscience conference, 2021
Modulation of system xc- mediated glutamate release in glioblastoma multiforme. Eastern Virginia Medical School Graduate Student Research Conference. Norfolk, Va., 2020
Extracellular matrix modulates system xc- (SXC) mediated glutamate release from gliomas via CD44. Society for Neuroscience Conference, Washington, D.C., 2017
Publications
Martin, J. Sontheimer, H. (2021) The roles of CD44 and EGFR in regulating system xc- mediated glutamate release in glioblastoma multiforme. In preparation.
Umans, R.A., Martin, J., Harrigan, M., Patel, D., Powell, M., Roshandel, A., Busch, C., Chaunsali, L., Smyth, J., Oestreich, K., & Sontheimer, H. (2021) The Transcriptional Regulation of Amino Acid Transport by P53 in Glioma. In preparation.
Mills W., Jiang, S., Martin, J., Woo, A., Bergstresser, M., Sontheimer, H. (2021) Disruption of astrocyte-vascular coverage induces an end foot replacement response that preserves neuromuscular coupling in vivo. In preparation.
Ceci A., Muñoz-Ballester C., Tegge A., Brown K.L., Umans R.A., Michel F.M., Patel D., Tewari B., Martin J., Alcoreza O., Maynard T., Martinez-Martinez D., Bordwine P., Bissell N., Friedlander M., Sontheimer H., Finkielstein C.V. (2021 ) Development and Implementation of a scalable and versatile FDA-Emergency Use Authorization test for COVID-19 diagnostics in rural communities. Nature. In review.