Metabolic Regulation of Ferroptosis in Pancreatic Cancer
dc.contributor.author | Kremer, Daniel | |
dc.date.accessioned | 2020-10-04T23:35:39Z | |
dc.date.available | NO_RESTRICTION | |
dc.date.available | 2020-10-04T23:35:39Z | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/163213 | |
dc.description.abstract | Pancreatic ductal adenocarcinoma (PDA) is a notoriously deadly disease having the lowest 5-year survival rate of any major cancer, owing to a lack of effective therapeutic options. A growing body of evidence demonstrates that PDAs reprogram their metabolism to support growth and survival in response to a harsh metabolic tumor environment. This work studies the hypothesis that metabolism can reveal novel therapeutic targets. Uncovering novel nutrient vulnerabilities could provide new ways to target PDA selectively. The goals of this work were two-fold. First, we developed analytical methods to identify metabolic changes in PDA and other biological samples. Employing mass spectrometry metabolomics, we profiled over two hundred metabolites in a single experiment across heterogeneous biological samples and experimental conditions. A meta-analysis of these metabolomics studies revealed insights into metabolite reproducibility, providing analytical benchmarks for quality control. Moreover, through systematic analysis we identified stable and dynamic metabolites, where dynamic metabolites play numerous roles in modulating gene expression and signaling. Together, this work provides benchmarks for metabolomics method development and robust analytical frameworks. Second, we examined nutrient vulnerabilities in PDA to identify novel therapeutic opportunities. We found that pancreatic cancer cells were highly sensitive to cystine deprivation. Cystine was required for the biosynthesis of two versatile redox co-factors, glutathione and coenzyme-A. Starving pancreatic cancer cells and tumors from cysteine triggered ferroptosis: an oxidative, iron-dependent, non-apoptotic form of cell death. Inhibiting cystine metabolism was well tolerated in mice and showed substantial anti-tumor activity, suggesting a new therapeutic strategy for PDA. In addition to identifying cystine as a metabolic vulnerability, we previously described that pancreatic cancers depend on a cytosolic aspartate aminotransaminase (GOT1)-dependent pathway for redox balance. Inhibiting GOT1 slowed the growth of PDA cells and tumors. We sought to identify metabolic dependencies induced by GOT1 inhibition as a strategy to kill PDAs selectively. We found cystine, glutathione, and lipid antioxidant function were metabolic susceptibilities following GOT1 suppression. Targeting these metabolic nodes triggered ferroptosis in synergy with GOT1 and delayed tumor growth. This effect was due to labile iron release, which augments ferroptosis sensitivity. Together, this work describes the development of mass spectrometry metabolomics tools and reveals how metabolism and ferroptosis are linked. This work presents new methods to study ferroptosis in diverse model systems, reconciling long-standing limitations in the field. We identify several metabolic nodes governing ferroptosis susceptibility, building upon the notion that ferroptosis is a metabolically-coupled form of cell death. Finally, we discuss several strategies to harness ferroptosis for therapy that could lead to novel treatments for PDA. | |
dc.language.iso | en_US | |
dc.subject | pancreatic cancer | |
dc.subject | ferroptosis | |
dc.subject | metabolism | |
dc.title | Metabolic Regulation of Ferroptosis in Pancreatic Cancer | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Chemical Biology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.contributor.committeemember | Lyssiotis, Costas Andreas | |
dc.contributor.committeemember | Banerjee, Ruma | |
dc.contributor.committeemember | Burant, Charles | |
dc.contributor.committeemember | Cierpicki, Tomasz | |
dc.contributor.committeemember | Fearon, Eric R | |
dc.subject.hlbsecondlevel | Oncology and Hematology | |
dc.subject.hlbsecondlevel | Physiology | |
dc.subject.hlbtoplevel | Health Sciences | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/163213/1/dmkremer_1.pdf | en_US |
dc.identifier.orcid | 0000-0001-6224-0550 | |
dc.identifier.name-orcid | Kremer, Daniel; 0000-0001-6224-0550 | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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