Unraveling The Effects of Aerobic Exercise and Erk5 Signaling In The Solid Tumor Microenvironment Using Murine Models

<p>Solid tumors are comprised of multiple cell types which communicate and work together to promote tumor progression. Advances in the treatment of solid tumors have armed clinicians with more efficacious pharmacologic agents and combinations. However, a focus on drug adjuvants in the treatment of solid cancer has left gaps in knowledge regarding non-pharmacologic treatment adjuvants, like aerobic exercise. The current dissertation investigates pharmacologic and non-pharmacologic based approaches to remodel the solid tumor microenvironment landscape and alter therapeutic efficacy. We disassemble compartments of the tumor microenvironment, including tumor vasculature and immune infiltrate, using mouse models and single cell techniques, to elucidate the effects of aerobic exercise and ERK5 signaling. We found that aerobic exercise normalizes tumor vasculature and improves chemotherapy efficacy in certain tumor models and that the ERK5 axis regulates tumor vascular permeability. By utilizing a novel mouse model, we demonstrated that knockout of endothelial cell specific ERK5 causes vascular inflammation and eventual death of mice. We then explored the role of exercise in vascular inflammation and tumor immune cell infiltrate in melanoma models finding that exercise improved tumor vasculature and upregulated an endothelial adhesion molecule across models, but differentially regulated hypoxia and the immune response. A deeper characterization revealed modulation in the number and phenotype of tumor infiltrating CD8 T cells and myeloid cells by exercise, including a change in macrophage polarization. Transgenic mice lacking ERK5 S496 phosphorylation presented a reversal in the effects of exercise in the tumor microenvironment, revealing a role of ERK5 in exercise-induced tumor microenvironment remodeling. Finally, we investigated the utility of exercise in combination with immune checkpoint blockade for the treatment of melanoma and demonstrate that successful combination will be complex to achieve. These findings illustrate the magnitude by which exercise alters solid tumor function, reveal an exercise-dependent mechanism of tumor microenvironment remodeling, and characterize novel roles of ERK5 in the tumor microenvironment.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2022

Authors dc:creator

• Savage, Hannah
• <p>0000-0003-4680-4656</p>

Contributors dc:contributor

• Keri Schadler
• Jun-ichi Abe
• Michelle Barton

• Solid tumors
• Tumor microenvironment
• Aerobic exercise
• Tumor vasculature
• Tumor immunology
• Cellular and Molecular Physiology
• Exercise Physiology
• Neoplasms
• Translational Medical Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1203

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2260