Studies Of The Molecular Mechanisms Underlying Cancer Stem Cells And The Transformed Metabolic Phenotype
Intense research throughout recent decades has significantly expanded our knowledge of the complexities that make cancer a highly diverse and therapeutically challenging disease. Recently, cancer stem cells (CSCs) and de-regulated cellular metabolism have become appreciated for their crucial roles in the development, growth, and therapy resistance of tumors, and are now being pursued as therapeutic targets for the treatment of cancer. To better understand how these oncogenic events contribute to tumor malignancy, I carried out a mechanistic analysis of the CSC marker aldehyde dehydrogenase 1A3 (ALDH1A3) and the GTP-binding protein/crosslinking enzyme tissue transglutaminase (tTG), two proteins suspected to have key roles in tumor initiation and the development of the malignant state, in glioma stem cells (GSCs). Additionally, I examined the contributions of two isoforms of glutaminase (GLS), given the critical role of elevated glutamine metabolism in maintaining the transformed state. In delineating the role of ALDH1A3 in GSCs, I discovered that it is an important regulator of gene expression through the production of retinoic acid (RA). Specifically, I demonstrated that the expression of tTG is induced downstream of ALDH1A3 via RA in highly aggressive GSCs. Furthermore, targeting tTG results in a dramatic reduction in the self-renewal of these cells, suggesting that it may be a viable therapeutic target in ALDH1A3 + GSCs. Finally, I showed that combination therapies including a tTG inhibitor and radiation or chemotherapy are cytotoxic, indicating that tTG inhibitors enhance the effects of standard glioma therapies. Work described in this thesis has also been directed toward understanding the roles of different splice variants of the metabolic enzyme GLS in cancer cell growth. An important question in the field has concerned whether the two known GLS splice variants, glutaminase C (GAC) and kidney-type glutaminase (KGA), have redundant or opposing functions. This becomes especially relevant when considering the importance of targeting one or both of these enzymes when designing strategies to inhibit the metabolic reprogramming of cancer cells. Here, I show that although KGA is expressed at low levels in cancer cells relative to GAC, these isoforms are functionally redundant in their abilities to support the transformed metabolic phenotype.
Cancer stem cells; Cancer metabolism; Cancer therapies
Emr,Scott David; Linder,Maurine E.
Ph.D. of Biochemistry
Doctor of Philosophy
dissertation or thesis