Date of Award

4-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Agricultural and Biological Engineering

First Advisor

Jenna Rickus

Committee Chair

Jenna Rickus

Committee Member 1

Sherry Voytik-Harbin

Committee Member 2

Kari Clase

Committee Member 3

Robin Bentley

Committee Member 4

Karen Pollok

Abstract

Glioblastoma (GBM) is a highly invasive brain cancer characterized by poor prognosis. Despite significant efforts by the basic and clinical research community our understanding of GBM progression and recurrence has been incremental. Improvements in therapeutic response have been dismal, and GBM continues to be the deadliest tumor of the central nervous system, with patient average survival rate of 12 months. Synergistic relationships that the tumor cells establish with the brain microenvironment have been proven fundamental for successful tumor progression and maintenance. Yet, many in vitro GBM studies are performed in formats that fail to recapitulate the most essential component of the tumor microenvironment.

In this work we aim to describe the influence of multiple features of the tumor microenvironment on GBM migration characteristics and response to drug treatment. Our approach involved the development of a 3D in vitro tissue model that recapitulates the cellular, chemical and mechanical features of brain microenvironment. To assess the influence of the physical properties of the extracellular matrix (ECM) on GBM migration we developed a matrix of hyaluronan supported by collagen with embedded microfibers to simulate the composition of brain ECM and the topographical cues of vasculature. Comparison of this model with Matrigel and collagen type-I showed that GBM exhibits different migration modes such as collective expansion, multicellular strands, and single cell migration as a response to the ECM composition and stiffness. Further incorporation of brain stromal cells as astrocytes and endothelial cells into the model showed that presence of astrocytes increased the migration of all GBM cell lines studied, however presence of endothelial cells only increased the migration of glioblastoma stem-like cells. Evaluation of the cytotoxic effect of multiple drugs on GBM was performed using our 3D model. Presence of extracellular matrix and stromal cells reduced the sensitivity of stem-like GBM cells to drug treatments. Our specific focus was on anti-STAT3 therapy and data obtained in the 3D model showed that the microenvironment regulates STAT3 activation as well as response to STAT3 drug targeting.

This work supports the fundamental role of the 3D-microenvironment as a modulator of GBM behavior and provides a consistent and tunable in vitro platform to be used in GBM studies for a more realistic understanding of in vivo cancer progression and response to therapy.

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