Advisory Committee Chair
Anita B Hjelmeland
Advisory Committee Members
Ichiro Nakano
Ralph D Sanderson
Christopher D Willey
George Y Gillespie
Document Type
Dissertation
Date of Award
2020
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Glioblastoma multiforme (GBM) is a highly invasive, highly vascularized, and heterogeneous malignant tumor of the brain. Due to the highly infiltrative phenotype of GBM, surgery often leaves behind residual tumor cells. In many cases, recurrence occurs close to the surgical margin suggesting the role of these remaining cells in promoting tumor aggressiveness. Rapidly growing tumor creates subsequent hypoxic, and hypovascular core due to limited nutrients, whereas tumor cells in the leading edge have access to nutrients from vasculature enriched microenvironment. Studies have identified the cellular and molecular heterogeneity between the tumors in core and edge. Still, their mechanisms of intercellular crosstalk remain poorly understood. The two studies presented in this dissertation focused on identifying the molecular mechanisms regulating the intratumoral spatial heterogeneity in GBM. In the first set of studies, we uncovered paracrine crosstalk from core cells that provokes malignancy and therapy resistance of edge cells. These phenotypic alterations were initiated by HDAC1 signaling in GBM core cells by secreting the soluble form of CD109 protein, which subsequently affected edge cells. Functional in vitro and in vivo studies using shRNA targeting of HDAC1 and AR42, a class I and II HDAC inhibitor, showed that the inhibition of this signaling pathway significantly decreased cell and tumor growth in core cells. Core cells that remain after surgery can significantly enhance the proliferation of edge cells, and HDAC1 inhibitors can effectively eliminate core GBM cells. Together, these findings demonstrate the critical role of intracellular communication between regionally different populations of GBM cells in tumor recurrence. Our second set of studies investigated the molecular signaling emanating from vascular endothelial (VE) cells in GBM. We identified endocan as one of the molecules secreted by tumor associated VE cells. We discovered a critical role for endocan as a regulator of tumor angiogenesis, edge-like phenotype, and radioresistance in GBM cells. We found PDGFR, a receptor tyrosine kinase, is a novel receptor for endocan and validated the activation of PDGFR and downstream signaling pathways such as PI3K and Myc. We also discovered that endocan is physiologically modulated by radiation therapy, and it protects GBM cells from undergoing radiation-induced apoptosis and cell death in vitro. Taken together, this study implicates endocan as an important molecule in promoting angiogenesis, spatial heterogeneity, and radioresistance in GBM. Collectively, the work establishes two novel regulatory mechanisms that highlight the importance of intra-cellular and inter-cellular crosstalk in the GBM microenvironment. We demonstrated the role of residual GBM core cells in promoting tumor aggressiveness in edge cells via the HDAC1-CD109 axis. We also discovered a novel regulatory mechanism of VE cell secreted endocan in promoting angiogenesis and therapy resistance in GBM. These findings are important because they enhance our knowledge of GBM tumorigenesis and provide potentially valuable new targets for anti-tumor therapy.
Recommended Citation
Bastola, Soniya, "Molecular Regulation Of Glioblastoma Spatial Heterogeneity And Therapeutic Resistance" (2020). All ETDs from UAB. 691.
https://digitalcommons.library.uab.edu/etd-collection/691