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Joelle Martin's Dissertation Defense (5/11/2021): Modulation of system xc- mediated glutamate release in glioblastoma multiforme via the extracellular matrix: the agony and the xCTasy

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Joelle Martin

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.