Author ORCID Identifier

https://www.orcid.org/0000-0003-4670-3898

Date of Graduation

8-2019

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Arvind Rao

Committee Member

Krishna Bhat

Committee Member

Jason Huse

Committee Member

Ganesh Rao

Committee Member

Vicki Huff

Committee Member

Ken Chen

Abstract

Diffuse high grade gliomas are complex and lethal neoplasms of the adult central nervous system that are driven by a range of genetic and epigenetic alterations. Molecular classification of these tumors has identified different transcriptional subtypes, the most notable being Proneural (PN) and Mesenchymal (MES) classes. The most aggressive forms of the disease have a Mesenchymal expression signature, with reported PN-to-MES transition occurring with tumor progression. Master regulatory analysis has identified the transcriptional co-activator TAZ (WWTR1) as a major driver of the MES transition. Overexpression of this single protein in glioma stem cells has been shown to drive a transition from a PN to MES cell state. In this study, we explore in depth the consequences of high TAZ expression in clinical glioma samples. We show that TAZ-high gliomas associate with immune infiltration and extracellular matrix genes, whereas TAZ-low gliomas associate with neuronal development genes. Furthermore, TAZ overexpression causes widespread epigenetic alterations in the cell, with consequent silencing of neuronal differentiation factors and an activation of mesenchymal regulators. Directed differentiation of glioma stem cells towards the post-mitotic neuronal state have been shown to be efficient strategies to battle this disease. By establishing the role of TAZ in suppressing the neuronal state in these cells, we argue that silencing of TAZ and/or its effector molecular complexes through therapeutics is a viable strategy. Given that TAZ has been found to be largely dispensable for normal tissue homeostasis, directed targeting of this protein is an attractive potential avenue in finding a cure for GBM.

Keywords

GBM, TAZ, gliomas, proneural to mesenchymal transformation, epigenetics, ChIP-seq

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