Kailee David
BME PhD Proposal Presentation

Date: 2025-09-25
Time: 2:30pm-4:30pm
Location / Meeting Link: UAW 2100

Committee Members:
Dr. Rafael Davalos, PhD (Advisor); Dr. David Myers, PhD; Dr. Annirudh Sarkar, PhD; Dr. Irving Coy Allen, PhD; Dr. Julie Gehl, MD


Title: Investigating the Spatiotemporal Dynamics of Electroporation-Induced Cell Death Mechanisms to Control the Immune Response

Abstract:
Conventional cancer therapies including surgical resection, chemotherapy, and radiotherapy have shown limited progress in enhancing patient survival rates across decades of research. Immunotherapies complement common therapies to enhance the immune response; however, they are not as effective for treating solid tumors. Thermal ablation is a potential solution to eliminate the bulk tumor; however, there are substantial difficulties when it comes to preventing damage to healthy tissue outside of the targeted malignancy. These procedural risks also stem from the proximity of tumors to intricate anatomical structures such as blood vessels and nerves. Additionally, concerns have arisen regarding recurrence in advanced stages of cancer due to residual cells or metastases originating from the primary tumor. These roadblocks necessitate a therapy capable of targeting the primary malignancy and inducing an immune response to clear out remaining tumor cells. Irreversible electroporation (IRE) capitalizes upon the shortcomings of common treatment strategies as it can protect surrounding structures and allows for precise treatment margins tailored to the targeted tumor. This therapeutic intervention is a non-thermal ablation technique utilizing electrical pulses to permeabilize the cell membrane, consequently leading to cell death. IRE has been shown to elicit an inflammatory response, suggesting a potential role in modulating tumor immunity. The strength of this response following electroporation is dictated by the mechanisms of cell death as they are either pro-inflammatory or non-inflammatory. However, the specific spatiotemporal dynamics of the cell death pathways after electroporation (i.e. apoptosis, necrosis, pyroptosis, ferroptosis, etc.) remain poorly understood. This dissertation aims to fill this critical knowledge gap by systematically characterizing the mechanisms of cell death activated by IRE to optimize immune-modulating ablation therapy. We hypothesize that different electric field intensities and pulsing parameters result in region-specific activation of distinct cell death pathways, which in turn influence the immune response and overall treatment efficacy. Preliminary immunoassay results indicate electric field strength and pulse length dependency when eliciting regulated forms of cell death such as apoptosis and pyroptosis. The following aim will utilize high-resolution confocal imaging of in vitro 3D tissue mimicking models to visualize and quantify several mechanisms over time under varying pulsing conditions. The final aim will be to characterize the bioelectric properties of cells as they die to analyze cellular alterations following electroporation. By providing a detailed spatiotemporal representation of cell death mechanisms in response to IRE, this research will enhance the understanding of tumor-immune interactions and inform the development of optimized ablation protocols.