Lauren Liebman
BME PhD Defense Presentation
Date: 2023-11-30
Time: 3pm
Location / Meeting Link: IBB Suddath Room (1128) / https://emory.zoom.us/j/96655461798?pwd=Skp6bUxnVm12a0ZZQmxPbVNxbmtZUT09
Committee Members:
J. Brandon Dixon, PhD (Advisor); Edward Botchwey, PhD; Zachary Buchwald, MD/PhD; Andres Garcia, PhD; Johnna Temenoff, PhD
Title: Targeting the Draining Lymphatic Network as a Regulator of Melanoma Growth
Abstract:
The lymphatic system is a complex network of lymph nodes and lymphatic vessels that performs crucial functions in human health and disease. In the context of cancers, including melanoma, the lymphatic system plays established roles in metastasis and immune suppression. However, recent work has demonstrated involvement of the tumor-draining lymph node (TDLN) in generating antitumor immunity. We hypothesize that, like the TDLN, tumor-draining lymphatic vessels may have key contributions to tumor control. While many targeted platforms exist to deliver therapies to lymph nodes, strategies to specifically modulate lymphangiogenesis or lymphatic vessel pumping function remain understudied. Therefore, in this work we investigate the role of tumor-draining lymphatic vessels and identify therapeutic strategies to improve their function. In Aim 1, we utilized a novel murine melanoma model in which we surgically disrupted the lymphatic vessel network draining from the tumor to the TDLN while leaving the TDLN intact. Via noninvasive imaging of lymphatic transport, measurements of tumor growth kinetics, and histological analyses, we investigated the effects of lymphatic vessel excision surgery on tumor progression and pathology. We also identified resulting changes in tumor-infiltrating immune cell populations after disruption of the lymphatic vessel network. Then, in Aim 2, we evaluated the efficacy of multiple therapeutic strategies, namely lymphangiogenic protein VEGF-C, mesenchymal stem cells engineered to overexpress VEGF-C, lymphatic endothelial cell-specific lipid nanoparticles loaded with VEGF-C mRNA, and a drug-loaded lymphatic-targeted hydrogel, to improve lymphatic vessel pumping function and reduce hallmarks of lymphatic injury in vivo. Overall, our findings indicate a critical role for tumor-draining lymphatic vessels in melanoma control, and support the use of lymphatic-targeted therapeutic strategies to enhance lymphatic function.