Investigating the Cell-Autonomous Role of Autophagy in Colon Cancer and the Reliance of Mitophagy for Growth
dc.contributor.author | Devenport, Samantha | |
dc.date.accessioned | 2020-01-27T16:26:38Z | |
dc.date.available | NO_RESTRICTION | |
dc.date.available | 2020-01-27T16:26:38Z | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/153479 | |
dc.description.abstract | Colorectal cancer (CRC) is the third leading cause of cancer related deaths worldwide. Cancer cells modify normal cell functions to adapt to the surrounding tumor microenvironment. Autophagy is a basic cell function used to degrade organelles, aggregated proteins, and nutrients to recycle for cellular use. In cancer, autophagy is known to play both tumor promoting and suppressive roles. In colon cancer, autophagy can enhance or inhibit tumor growth and the function is often tumor stage and context dependent. A more in-depth understanding of how autophagy alters tumor growth is necessary to better develop treatments for patients with colon cancer. Previous literature has shown a cross-talk between epithelial autophagy and the intestinal immune response. This dissertation uncovers a novel cell-autonomous role for autophagy in colon cancer independent of the immune system. While autophagy is classically known to provide nutrients to the cell, the cellular components that are targeted for breakdown and under what context they are targeted is not known in colon cancer. Tumor cell growth is inhibited following autophagy loss, but normal colon epithelia are not impacted by inhibition suggesting a tumor selective reliance on autophagy. Under nutrient stress tumor cells employ mitophagy, a selective form of autophagy that targets mitochondria for breakdown. Inhibition of PINK/PRKN directed mitophagy significantly reduces cell growth. Lastly, I assessed cell type specificity of autophagy in CRC. Autophagy is known to have differential roles in epithelial sub-types. In inflammatory bowel disease, loss of autophagy specifically alters Paneth cell function. To explore the role of autophagy in colon cancer, I utilized single-cell RNA sequencing to investigate changes in autophagy in epithelial cells in colon cancer. In a sporadic tumor model with loss of Apc, p53, and KrasG12D I performed single-cell analysis on colon tissue. I found that enterocytes express genes associated with increased autophagy in comparison to goblet cells or enteroendocrine cells. This data suggests a specific increase in autophagy in tumor enterocytes. Further single-cell analysis at different stages of tumor development and focus on different cell types will begin to uncover how colon tumors are modulated by autophagy. This dissertation uncovers the cell type specificity and cell-autonomous role for autophagy in colon cancer. Further in-depth studies are needed to assess the role of tumor stage and mutational load in the requirement of autophagy in colon cancer. I have identified that tumor cells rely on mitophagy for growth and lay the foundation for therapies targeting autophagy or mitophagy in CRC | |
dc.language.iso | en_US | |
dc.subject | Investigating the Cell-Autonomous Role of Autophagy in Colon Cancer and the Reliance of Mitophagy for Growth | |
dc.title | Investigating the Cell-Autonomous Role of Autophagy in Colon Cancer and the Reliance of Mitophagy for Growth | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Cellular & Molecular Biology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.contributor.committeemember | Shah, Yatrik M | |
dc.contributor.committeemember | Fearon, Eric R | |
dc.contributor.committeemember | Lee, Jun Hee | |
dc.contributor.committeemember | Pasca Di Magliano, Marina | |
dc.subject.hlbsecondlevel | Molecular, Cellular and Developmental Biology | |
dc.subject.hlbtoplevel | Health Sciences | |
dc.description.bitstreamurl | https://deepblue.lib.umich.edu/bitstream/2027.42/153479/1/sdevenpo_1.pdf | |
dc.identifier.orcid | 0000-0001-7188-5393 | |
dc.identifier.name-orcid | Devenport, Samantha; 0000-0001-7188-5393 | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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