Advisor(s)
Anita Hjelmeland
Committee Member(s)
Jessy Deshane
Peter King
Ralph Sanderson
Sara Cooper
School
College of Arts and Sciences
Document Type
Dissertation
Department (new version)
Biology
Date of Award
9-9-2024
Abstract
GBM is characterized by aggressive growth and therapy resistance, with a median survival of 14 months despite treatment. Brain tumor initiating cells (BTICs), as a subset of stem-like GBM cells known for their invasiveness, therapy resistance, and immune evasion. BTICs have increased GLUT3 expression, which is correlated with poor patient prognosis. This study identifies a novel role of GLUT3 in GBM invasion, distinct from its canonical function in glucose uptake and glycolysis, as well as a mechanism by which GLUT3 contained in exosomes promotes monocyte migration. Our data show that blocking phosphorylation of GLUT3 at T492, abolishes its pro-invasive phenotype, while a phosphomimetic induces invasion. Specifically, mutation of T492 alone is sufficient to inhibit GLUT3-mediated invasion in GBM cells, both in vitro and in vivo. Importantly, these alterations in GLUT3 do not affect glucose uptake or glycolytic flux, suggesting a glucose-independent mechanism. Further investigations reveal a PKC-nu/PKD3-MMP13 pathway downstream of GLUT3 phosphorylation at T492, promoting invasion. Additionally, we delve into the impact of BTIC-derived exosomes, containing GLUT3, on monocyte migration, revealing a significant role in the modulation of the tumor microenvironment. Monocytes, key players in the immune response, are known to migrate to sites of inflammation or injury, where they can differentiate into macrophages and contribute to various physiological processes, including tissue repair and immune surveillance. Exposure to GLUT3-overexpressing BTIC-derived exosomes significantly enhances monocyte migration compared to exposure to control exosomes. Transcriptomic analysis highlights alterations in gene expression patterns associated with monocyte migration, including a GDF-15- MMP12pathway as a potential mediator of the observed increase in migration. Thus, we provide compelling evidence that BTIC-derived exosomes, enriched with GLUT3, play a pivotal role in promoting monocyte migration through a signaling cascade involving GDF-15 and MMP12. These finding highlight the intricate role of GLUT3 in promoting GBM invasion, as well as the interplay between tumor cells and immune cells in the tumor microenvironment.
ProQuest ID
Recommended Citation
Williford, Sarah Elizabeth, "Elucidating The Role Of Glut3 In Glioblastoma Invasion And The Tumor Microenvironment" (2024). All ETDs from UAB. 7576.
https://digitalcommons.library.uab.edu/etd-collection/7576
