The current project builds on our previous efforts to define and characterize cancer cells of origin within the epidermis. We demonstrated that hair follicle stem cells are cells of origin for squamous cell carcinoma, and that the inherent quiescence of these cells acts as a tumor suppressor mechanism. The current proposal seeks to understand the role metabolism plays in both maintaining HFSCs, and also in their ability to initiate tumorigenesis. Our preliminary data suggests that HFSCs possess a unique mode of metabolism, and we seek to understand if this metabolic state is necessary to maintain these cells as quiescent, multipotent stem cells. We will extend our characterization of HFSCs to include metabolomics approaches and determine whether alteration of metabolic pathways disrupts their self-renewal or differentiation. Furthermore, with our inducible tumor initiation model, we will be able to characterize the full extent of any metabolic transitions that occur in vivo for the first time. We expect that these experiments will uncover novel mechanisms that regulate HFSC biology, and perhaps even point towards new targeted therapeutics for HFSC initiated tumors.
We propose to understand how the metabolic state of hair follicle stem cells controls their quiescence and ability to initiate tumorigenesis. We will use gain and loss of function approaches to target particular metabolic nodes to understand how they promote or inhibit stem cell activation or the ability of stem cells to initiate tumorigenesis. This work will not only uncover the role metabolic regulation plays in normal tissue, but also how this regulation can influence tumor initiation and progression.
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| Sullivan, William J; Mullen, Peter J; Schmid, Ernst W et al. (2018) Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization. Cell 175:117-132.e21 |
| Jelinek, David; Flores, Aimee; Uebelhoer, Melanie et al. (2018) Mapping Metabolism: Monitoring Lactate Dehydrogenase Activity Directly in Tissue. J Vis Exp : |
| Coller, Hilary A (2018) DNA replication licensing in stem cells: Gatekeeping the commitment to proliferation. J Cell Biol 217:1563-1565 |
