Salivary adenoid cystic carcinoma (ACC) is prone to perineural invasion, late recurrence, and distal metastases, with 20-year survival of only 10%. Research defining new targets in ACC has lagged largely due to a dearth of in vitro models. In this thesis, a neurogenic gene signature intrinsic to ACC was characterized revealing genes involved in maintenance, differentiation, and function of non-cancerous neural crest stem cells, including TrkC and SOX10. Analyses of gene expression across tumor types revealed that melanoma, neuroblastoma, glioblastoma, and basal-like breast cancer expressed SOX10 and several SOX10 co-expressed genes, suggesting that tumors derived from cells originating in the neural crest may contain similar populations of stem-like cells. Examination of TrkC signaling revealed that TrkC supported cell migration, invasion, and ACC tumor growth, and that ACC cells produced the TrkC ligand. Optimization of newly-designed culturing techniques allowed for the first time establishment of ACC cell cultures from xenograft and primary ACC specimens. Gene expression analysis revealed that CD133 was co-expressed with SOX10, and remarkably, it marked a subpopulation of ACC cells that preferentially expressed NOTCH1 and SOX10, formed spheroids, and initiated tumors in nude mice. Depletion of NOTCH1 or pharmaceutical inhibition of Notch signaling depleted CD133+ cells, sensitized CD133+ cells to radiation, and suppressed spheroidogenesis and xenograft tumor formation. Optimization of culture techniques provides a framework for future experimentation, and identification of a stem-like subpopulation in ACC suggests that targeting signaling pathways critical for stem cell survival or behavior may provide a new avenue to ACC therapy.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03282016-104528 |
| Date | 04 April 2016 |
| Creators | Panaccione, Alexander Colin |
| Contributors | Albert B. Reynolds, Alissa M. Weaver, Linda J. Sealy, Wendell G. Yarbrough |
| 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-03282016-104528/ |
| Rights | unrestricted, 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. |
Page generated in 0.0072 seconds