Identifying targetable metabolic vulnerabilities for treating brain cancers
| dc.contributor.author | Martell, Emma | |
| dc.contributor.examiningcommittee | Werbowetski-Ogilvie, Tamra (Biochemistry and Medical Genetics) | |
| dc.contributor.examiningcommittee | Logue, Susan (Human Anatomy and Cell Science) | |
| dc.contributor.examiningcommittee | Saleem, Ayesha (Kinesiology and Recreation Management) | |
| dc.contributor.examiningcommittee | Gallo, Marco (Baylor College of Medicine Houston, TX) | |
| dc.contributor.supervisor | Sharif, Tanveer | |
| dc.date.accessioned | 2025-01-09T21:07:00Z | |
| dc.date.available | 2025-01-09T21:07:00Z | |
| dc.date.issued | 2025-01-02 | |
| dc.date.submitted | 2025-01-02T23:46:49Z | en_US |
| dc.degree.discipline | Human Anatomy and Cell Science | |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | |
| dc.description.abstract | Brain tumors account for only 2% of all cancer cases but cause the fourth-highest number of years of life lost to cancer. They are the leading cause of cancer-related death in children, with medulloblastoma (MB) being the most common pediatric brain malignancy. MB tumors arise from errors in early fetal brain development, where the highly aggressive subgroup, group 3 (G3), closely resembles primitive neural stem cells. In adults, glioblastoma (GBM) is the most common brain cancer and has a poor 5-year survival rate of less than 5%. GBM tumors display stem-like cell characteristics and mimic neurodevelopmental hierarchies. Stem-like cancer cells are very aggressive and often less responsive to therapies, posing a major treatment challenge. Survivors of brain cancer often suffer life-long health problems and neurocognitive impairments due to the tumor or cytotoxic treatments. Many patients experience tumor recurrence following initial treatment, with recurrent tumors being almost universally fatal. Hence, there is a critical need for better and safer therapeutic options. Metabolic reprogramming has emerged as a critical hallmark of cancer. Metabolism can influence cell signaling networks that support tumor cell growth and alter cellular functions. Targeting abnormal metabolic phenotypes is an attractive therapeutic strategy, but it remains unclear how metabolism regulates the aggressive stem-like cell characteristics of brain tumors and helps them resist therapy. This thesis summarizes findings from three studies on the role of metabolism in regulating stem-cell identity and therapeutic responses in GBM and G3 MB brain tumors. The first study reveals a mechanism by which metabolism regulates the stability of the stemness factor and oncogene c-MYC in G3 MB, demonstrating the therapeutic potential of targeting this metabolic vulnerability. The second study explores the distinct metabolic features of GBM stem-like cells and identifies their compensatory responses to metabolic manipulations. The third study uncovers a metabolic adaptation in GBM following chemoradiotherapy that helps maintain stem cell identity by limiting differentiation through epigenetic reprogramming. Blocking this adaptation impaired tumor relapse and prolonged survival in pre-clinical animal models. These findings advance our understanding of metabolism in stem cell signaling networks and identify novel metabolic vulnerabilities for treating aggressive brain tumors. | |
| dc.description.note | February 2025 | |
| dc.identifier.uri | http://hdl.handle.net/1993/38771 | |
| dc.language.iso | eng | |
| dc.rights | open access | en_US |
| dc.subject | Brain Cancer | |
| dc.subject | Metabolism | |
| dc.subject | Medulloblastoma | |
| dc.subject | Glioblastoma | |
| dc.title | Identifying targetable metabolic vulnerabilities for treating brain cancers | |
| dc.type | doctoral thesis | en_US |
| local.subject.manitoba | no |