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Title: Glioblastoma cell behaviour : a study of chemically-induced cellular connectivity and 3D modelling of cellular migration
Author: da Silva, Barbara Luisa
ISNI:       0000 0004 7654 6341
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2018
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Glioblastoma multiforme (GBM) is the most common and deadliest brain cancer in adults. Despite considerable efforts at both bench and bedside, the average survival for GBM patients is only 14-15 months. This dismal prognosis stems from challenges in treatment and a malignant tumour biology. A key need in addressing GBM is to better understand and therapeutically target GBM cell invasion into the surrounding healthy brain tissue. Cytoskeletal remodelling and dynamics, mediated by ROCK effector proteins, play an important role in the ability of GBM cells to migrate. ROCK inhibition is being considered as potential cancer therapy; however, there is insufficient data examining a chemical pan-ROCK inhibition effect in the cellular context of GBM. I address this gap in the context of undifferentiated patient-derived brain tumour stem cell (BTSC) models. My results show that chemical ROCK pathway inhibition with several different compounds led to a reversible neurite-like outgrowth phenotype across three different patient-derived cell models. This phenotype was accompanied by a decrease in BTSCs motility, which enabled the cells to form an interactive multicellular network. Interestingly, ROCK inhibition did not alter the self-renewal ability or proliferation capacity of BTSCs. To further investigate this diffusive nature of GBM cells, I developed an in vitro 3D model that allows the study of GBM infiltration in real-time. My work demonstrates the ability of GBM spheres to spontaneously fuse with, and infiltrate, neural-like early-stage cerebral organoids (eCOs) with the use of stem cell culture-based organoid methodology. In addition, this 'hybrid' GBM tumour organoid possessed an invasive tumour compartment, which was specific to GBM cells. Thus, this self-assembly GBM tumour organoid may be used to identify anti-GBM invasion treatment approaches.
Supervisor: Wurdak, Heiko ; Short, Susan ; Cook, Graham Sponsor: Brain Tumour Research and Support across Yorkshire (BTRS)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available