All ETDs from UAB

Advisory Committee Chair

Christopher D Willey

Advisory Committee Members

Peter H King

Ryan C Miller

William J Placzek

Document Type

Thesis

Date of Award

2021

Degree Name by School

Master of Science (MS) Heersink School of Medicine

Abstract

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults. Despite decades of research, GBM has a median survival of approximately 14 months, necessitating the development of novel GBM therapeutics. The drug-development process has been hindered due to the lack of high-fidelity pre-clinical models. While in-vitro models of patient-derived xenografts (PDX) present an interesting approach to modeling GBM, they typically fail to incorporate the non-cancerous cells that support tumor growth and progression. Others have attempted to address this problem by using techniques such as 3D bioprinting to incorporate astrocytes and macrophages in an extracellular matrix; however, they used serum-containing media and classically polarized anti-inflammatory (M2) macrophages. The use of serum-containing media has been shown to cause GBM brain-tumor initiating cells (BTICs) to lose their stem-like properties, thus necessitating the development of serum-free media to support all components of these 3D constructs. Additionally, tumor-associated macrophages (TAMs) have been shown to have a distinct phenotype that does not closely resembles the M2 phenotype. In this study, we have demonstrated a novel method by which we can culture these 3D bioprinted constructs in serum-free media that supports the growth of GBM PDX cells, astrocytes, and macrophages. By using image cytometry and cytokine profiling, we have also identified a new method to polarize macrophages towards a tumor-supportive phenotype and that these macrophages differ in their cytokine expression from traditionally polarized macrophages. Together, these results highlight a more physiologically relevant method of modeling GBM that can be used to identify targetable pathways that can lead to the development of therapeutics that may one day enter the clinic in hopes of improving patient outcomes in GBM.

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