The Doctor of Philosophy Seminar and Examination of Kelsey Murphy

Biography

Kelsey studied chemistry at St. Lawrence University in Canton, NY, graduating in 2018. Her research career began at St. Lawrence under the mentorship of Dr. Samantha Glazier, where she studied DNA-binding thermodynamics and kinetics of anti-cancer drugs. Following graduation, Kelsey served in the Peace Corps in St. Vincent and the Grenadines. In the Peace Corps, Kelsey worked closely with the Vincentian Society for the Prevention of Cruelty to Animals as a veterinary surgical technician for spay/neuter clinics around the island. She then chose to pursue a career in veterinary medicine and research, and began research training at Virginia-Maryland College of Veterinary Medicine under the mentorship of Dr. Nick Dervisis. Under his mentorship, her work investigating tumor ablation therapies for the treatment of cancers in dogs and people has solidified her aspirations to pursue a career as a veterinary clinician-scientist. Following this research training, Kelsey continues to pursue her veterinary training in the DVM program at Tufts Cummings School of Veterinary Medicine. In the future, Kelsey hopes to impact both veterinary and human medicine through translational clinical research. In her free time, Kelsey enjoys hiking with her beloved dog Mikey, gardening and fueling her houseplant addiction, mountain biking, and exploring local restaurants with friends and family.

Funded by

• Virginia-Maryland College of Veterinary Medicine DVM/PhD Dual Degree Program
• National Institute of Health R01CA240476
• Internal Research Competition
• Center for Engineered Health
• Grayton Friedlander Fund

Awards and Academic Achievements

• Center for Engineered Health Seed Award 2022             
• BMVS Graduate Student Association Co-President 2022                                   
• Internal Research Competition Award 2022        
• BMVS Graduate Student Association Dual Degree Student Representative 2021
• The Honor Society of Phi Kappa Phi 2021
• Clark L. Gage Award for Excellence in Research 2018
• Chymist Honor Society 2018

Lay Language Abstract 

All cells secrete extracellular vesicles, which are packets of information that function as communication highways between cells. In cancer, tumor-derived extracellular vesicles (TDEVs) reprogram local and distant cells to support tumor growth. However, they have also been shown to change local and systemic functions, such as blood vessel function and immune response, after tumors are treated with therapeutics. Therefore, a full understanding of the role of TDEVs in how tumors communicate with the body after cancer treatment is necessary when developing new anti-cancer therapeutics. Here, in developing high-frequency irreversible electroporation (H-FIRE), a novel anti-tumor therapeutic for the treatment of malignant brain tumors, we explore how TDEVs released by brain cancer cells treated with H-FIRE interact with various cell types and structures in the body, and how these interactions may affect the response to treatment. Using a glioma model of primary brain cancer and a lung carcinoma model of brain metastases, we first explore how tumor cells may be able to recover from damage after treatment with H-FIRE. We discover that brain cancer cells treated with specific doses of H-FIRE recover cell damage and continue to proliferate, but cells treated with higher doses of H-FIRE cannot recover these functions. The fact that tumor cells may be able to recover after H-FIRE suggests that cancer cells may still secrete factors, such as TDEVs, that interact with cells in the microenvironment after tumor treatment. We investigated the role of TDEVs released by brain cancer cells treated with H-FIRE to determine whether they cause changes in surrounding cells and structures in the brain cancer microenvironment. We determined that brain cancer cells treated with H-FIRE release TDEVs that carry proteins different from those carried by TDEVs routinely released by untreated cells. We further found that these TDEVs disrupt the blood-brain barrier (BBB) endothelium in vitro, and are uniquely internalized by cells of the endothelium. When these TDEVs were administered to the brains of healthy rats, they were retained in the brain, clustered near the endothelium, and recruited immune cells from circulation into the brain. Conversely, TDEVs that were routinely released from the brain cancer cells, in the absence of H-FIRE treatment, exhibited none of these functions. Taken together, these results show that H-FIRE changes TDEVs in numerous ways: after H-FIRE, the TDEVs may gravitate toward particular organs and cell types, and recruit immune cells. All of these changes can impact the overall therapeutic response after H-FIRE, and may also be specifically optimized and targeted with additional therapeutics to make H-FIRE more effective for brain cancer.

Publications

Murphy, K.R., Aycock, K.N., Marsh, S., Hay, A.N., Athanasiadi, I., Bracha, S., Chang, C., Gourdie, R., Davalos, R.V., Rossmeisl Jr., J.H., Dervisis, N.G. Tumor-derived extracellular vesicles disrupt the blood-brain barrier endothelium following high-frequency irreversible electroporation. Under peer review.

Murphy, K.R., Hay, A.N., Rossmeisl Jr., J.H., Klahn, S., Vlaisavljevich, E., Tuohy, J., Davalos, R.V., Coutermarsh-Ott, S., Dervisis, N.G. Tumor ablation in veterinary oncology: a review. Hellenic Journal of Companion Animal Medicine. 2022; Vol 1, Issue 2.

Murphy KR, Aycock KN, Hay AN, Rossmeisl JH, Davalos RV, Dervisis NG. High-frequency irreversible electroporation brain tumor ablation: exploring the dynamics of cell death and recovery. Bioelectrochemistry. 2022; 144: 108001.

Presentations

Murphy, K. R., Aycock, K.N., Hay, A.N., Marsh, S., Chang, C., Bracha, S., Gourdie, R., Davalos, R.V., Rossmeisl, J.H., Dervisis, N.G. “High-frequency irreversible electroporation of glioma alters tumor-derived extracellular vesicles and disrupts the blood-brain barrier.” Poster presentation delivered at American Association for Cancer Research Annual Meeting. Orlando, Florida. April 18, 2023.

Murphy, K. R., Aycock, K.N., Hay, A.N., Marsh, S., Chang, C., Bracha, S., Gourdie, R., Davalos, R.V., Rossmeisl, J.H., Dervisis, N.G. “High-frequency irreversible electroporation of glioma alters tumor-derived extracellular vesicles to mediate blood-brain barrier disruption.” Oral presentation delivered at Virginia-Maryland College of Veterinary Medicine Biomedical and Veterinary Sciences 32^nd Annual Research Symposium. Blacksburg, Virginia. March 14, 2023.

Murphy, K. R., Aycock, K.N., Hay, A.N., Marsh, S., Chang, C., Bracha, S., Gourdie, R., Davalos, R.V., Rossmeisl, J.H., Dervisis, N.G. “Ready, aim, H-FIRE: novel bystander effect-mediated mechanisms of peritumoral BBB disruption induced by tumor-derived extracellular vesicles following H-FIRE brain tumor ablation.” Oral presentationdelivered at Virginia-Maryland College of Veterinary Medicine Biomedical and Veterinary Sciences Seminar. November 2, 2022.

Murphy, K. R., Aycock, K.N., Hay, A.N., Marsh, S., Chang, C., Bracha, S., Gourdie, R., Davalos, R.V., Rossmeisl, J.H., Dervisis, N.G. “Bystander effects of H-FIRE brain tumor ablation disrupt the blood-brain barrier endothelium via release of tumor-derived extracellular vesicles.” Poster presentation delivered at Veterinary Cancer Society Annual Meeting. Norfolk, VA. October 15, 2022.

Murphy, K. R., Aycock, K.N., Hay, A.N., Marsh, S., Chang, C., Bracha, S., Gourdie, R., Davalos, R.V., Rossmeisl, J.H., Dervisis, N.G. “Bystander effects of H-FIRE brain tumor ablation disrupt the peritumoral blood-brain barrier via release of tumor-derived exosomes.” Poster presentation delivered at International Precision Neuroscience Conference. Roanoke, Virginia. May 26, 2022.

Murphy, K. R., Aycock, K.N., Hay, A.N., Marsh, S., Chang, C., Bracha, S., Gourdie, R., Davalos, R.V., Rossmeisl, J.H., Dervisis, N.G. “Bystander effects of H-FIRE brain tumor ablation disrupt the peritumoral blood-brain barrier via release of tumor-derived exosomes.” Poster presentation delivered at the Fralin Biomedical Research Institute at VTC 2022 Cancer Research Alliance Retreat. Roanoke, Virginia. March 18, 2022.

Murphy, K. R., Aycock, K. N., Hay, A. N., Rossmeisl, J. H., Davalos, R. V., & Dervisis, N. G. “Exploring the dynamics of cell death and recovery associated with high-frequency irreversible electroporation brain tumor ablation.” Oral presentation delivered at the Virginia Cancer Research Conference. Richmond, Virginia. November 20, 2021

Murphy, K., Aycock, K., Hay, A., Bracha, S., Chang, C., Davalos, R., Rossmeisl, J,. Dervisis, N. “High-frequency irreversible electroporation-induced brain tumor cell death has distinct effects on blood-brain barrier endothelium.” Poster presentation delivered at Veterinary Cancer Society Annual Meeting. November 4, 2021.

Murphy, K., Aycock, K., Hay, A., Davalos, R., Rossmeisl, J., Dervisis, N.  “Investigation of blood-brain barrier disruption and tumor cell death dynamics induced by high-frequency irreversible electroporation brain tumor ablation.” Oral presentation delivered at Virginia-Maryland College of Veterinary Medicine Biomedical and Veterinary Sciences Seminar. November 3, 2021.

Murphy, K., Aycock, K., Hay, A., Davalos, R., Rossmeisl, J., Dervisis, N. Investigation of blood-brain barrier disruption induced by high-frequency irreversible electroporation brain tumor ablation. Oral presentation delivered virtually at the National Association of Veterinary Scientists Combined Degree Colloqium. August, 2021

Examination Graduate Committee

Major Advisor/Chair:

Nick Dervisis, DVM, PhD, DACVIM-Oncology
Associate Professor, Medical Oncology
Department of Small Animal Clinical Sciences

Graduate Advising Committee Members:

John H. Rossmeisl Jr., DVM, MS, DACVIM-Internal Medicine, Neurology
Associate Department Head Department of Small Animal Clinical Sciences, Dr. and Mrs. Dorsey Taylor Mahin Professor of Neurology and Neurosurgery
Department of Small Animal Clinical Sciences

Joanne Tuohy, DVM, PhD, DACVS-Small Animal
Assistant Professor, Surgical Oncology
Department of Small Animal Clinical Sciences

Rafael Davalos, PhD
Margaret P. and John H. Weitnauer Jr. Chaired Professor, ASME, BMES, NAI, and AIMBE Fellow
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology