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Caveolin-1: a mediator of Glioblastoma cell invasion and an independent negative biomarker of Glioblastoma patient survival

Moriconi, Chiara 2018. Caveolin-1: a mediator of Glioblastoma cell invasion and an independent negative biomarker of Glioblastoma patient survival. PhD Thesis, Cardiff University.
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Abstract

Glioblastoma multiforme (GBM) is a malignant and highly aggressive form of brain tumour, with extremely poor prognosis. One of its features is the ability of the tumour to invade through normal brain resulting in tumour relapse. Our hypothesis was that Caveolin-1 (Cav-1), a major component of the caveolae and recognized to be involved in a number of signalling pathways, has a key pro-invasive role in GBM. We pursued our hypothesis by inhibiting the expression of Cav-1 in different adult GBM cell lines using different genetic techniques (liposome shRNA, lentiviral shRNA and CRISPR). We found that Cav-1 drives clonogenicity (CHAPTER 3) and invasion in a combination of two- and three-dimensional models (CHAPTER 5). We focused our research on the invasion phenomenon and, in order to provide a robust quantification approach to study invasion in 3D spheroid assays, we developed (CHAPTER 4) a open-source semi-automated script, INSIDIA, available for all researchers in the community to use. This tool was used to quantify the impact of Cav-1 on invasive capacity. In in-vitro systems, we explored the impact of Cav-1 expression upon molecules associated with the invasion phenomenon (CHAPTER 5). We found Cav-1 to be associated with CTSB, MMP1 and UPA and receptors like UPAR and CD44, as well as AKT activation. Interrogating the “The Cancer Genome Atlas” (TCGA) database, we confirmed that Cav-1 is an independent biomarker of poor prognosis in GBM patients (CHAPTER 6). This clinical data also found association of genes that may cooperate with Cav-1, including CD44, ITGA3, VIM, CTSB, CTSL, TSP-1, TIMP1 and MT1MMP. Collectively this thesis provides strong in vitro and clinical data supporting that Cav-1 as a key molecule promoting GBM invasion, and further identifying Cav-1 as a potential drug discovery target in GBM.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Pharmacy
Subjects: Q Science > Q Science (General)
Uncontrolled Keywords: Glioblastoma, Invasion, Survival, Caveolin-1, Recurrence, CRISPR
Date of First Compliant Deposit: 14 March 2019
Last Modified: 14 Mar 2019 10:19
URI: http://orca.cf.ac.uk/id/eprint/120682

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