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Title page for ETD etd-03282016-104528


Type of Document Dissertation
Author Panaccione, Alexander Colin
URN etd-03282016-104528
Title Identification and Characterization of Neural-like Cancer Stem Cells in Salivary Adenoid Cystic Carcinoma
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Albert B. Reynolds Committee Chair
Alissa M. Weaver Committee Member
Linda J. Sealy Committee Member
Wendell G. Yarbrough Committee Member
Keywords
  • Cancer
  • Stem Cells
  • Salivary
  • Cell Biology
Date of Defense 2016-03-18
Availability unrestricted
Abstract
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.
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