Please use this identifier to cite or link to this item:
http://hdl.handle.net/11375/24374
Title: | Bi-directional vulnerability of brain tumors to Wnt signaling |
Authors: | Manoranjan, Branavan |
Advisor: | Singh, Sheila K |
Department: | Biochemistry and Biomedical Sciences |
Keywords: | glioblastoma;medulloblastoma;Wnt;beta-catenin;CD133;Bmi1;brain tumor-initiating cell;cancer stem cell |
Publication Date: | 2019 |
Abstract: | Brain tumors represent a leading cause of cancer mortality, of which medulloblastoma (MB) and glioblastoma (GBM) represent the most frequent malignant pediatric and adult brain tumors, respectively. The identification of a rare clonal population of cells, termed cancer stem cells (CSCs) or brain tumor-initiating cells (BTICs), as having the ability to initiate, proliferate, and maintain tumor growth has offered a developmental framework for studying MB and GBM. Evidence in support of cell signaling programs carried forward from brain development into oncogenesis have provided opportunities for BTIC-directed therapies targeting the key BTIC property of self-renewal. Given that neural stem cells (NSCs) must maintain a relative balance between self-renewal and differentiation, brain tumorigenesis may be conceptualized as a disease of unregulated BTIC self-renewal. In this work, I aim to demonstrate the re-emergence of self-renewal genes that regulate NSCs in BTICs, use the Wnt pathway as a model by which these genes may be regulated in a context-specific manner, and identify clinically tractable therapies directed at the overall BTIC self-renewal signaling machinery. Specifically, in Chapter 2, I describe the presence of a shared signaling program between NSCs and MB BTICs consisting of Bmi1 and FoxG1. In Chapter 3, I provide evidence in support of a context-specific tumor suppressive function for activated Wnt/β-catenin signaling in MB. Lastly, in Chapter 4, I demonstrate a CD133-AKT-Wnt signaling axis in which CD133 functions as a putative cell surface receptor for AKT-dependent Wnt activation in GBM. Overall, the body of this thesis offers a mechanistic model by which BTICs may be regulated and targeted to impair tumor growth and improve overall survivorship in childhood MB and adult GBM. |
URI: | http://hdl.handle.net/11375/24374 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Manoranjan_Branavan_2019April_PhD.pdf | 6.8 MB | Adobe PDF | View/Open |
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