Dysregulation of receptor tyrosine kinases (RTKs) contributes to cellular transformation and cancer progression by disrupting key metabolic signaling pathways. The EPHA2 RTK is overexpressed in aggressive forms of breast cancer, including the HER2+ subtype, and correlates with poor prognosis. However, the role of EPHA2 in tumor metabolism remains unexplored. This thesis sought to determine the mechanisms by which EPHA2 ligand-independent signaling promotes tumorigenesis in the absence of its prototypic ligand, ephrin-A1. We integrated in vivo and in vitro models of HER2-overexpressing breast cancer to demonstrate that loss of ephrin-A1 leads to upregulated glutamine metabolism and lipid accumulation that enhanced tumor growth. Global metabolic profiling of ephrin-A1-null, HER2-overexpressing mammary tumors revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis. Pharmacologic inhibition of glutaminase activity reduced tumor growth in both ephrin-A1-depleted and EPHA2-overexpressing tumor allografts in vivo. Mechanistically, we show that the enhanced proliferation and glutaminolysis in the absence of ephrin-A1 was attributed to increased RhoA-dependent glutaminase activity. EPHA2 depletion or pharmacologic inhibition of Rho, glutaminase, or fatty acid synthase abrogated the proliferative effects of ephrin-A1 knockdown. Together, these findings highlight a novel, unsuspected connection between the Ephrin-A1/EPHA2 signaling axis and tumor metabolism, and suggest potential new therapeutic targets in cancer subtypes exhibiting glutamine dependency.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03172016-102302 |
| Date | 30 March 2016 |
| Creators | Youngblood, Victoria Marie |
| Contributors | Jin Chen, Melissa Skala, Rebecca Cook, Barbara Fingleton |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03172016-102302/ |
| Rights | restrictone, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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