| Popis: |
For an increasing number of cancers, the cell of origin has been demonstrated to be theresident adult stem cell. One such cancer is squamous cell carcinoma, for which recentstudies in our lab traced its origin to the hair follicle stem cells. Malignant transformationis thought to coincide with a dramatic shift towards the use of glycolysis and establishmentof a ‘Warburg’ state – increased metabolism of glucose to lactate. How the Warburg Effectis established during tumor initiation and progression in vivo remains unclear. The currentconsensus is that the bulk of the energy generated in most adult tissue cells is created byoxidative phosphorylation, while more highly proliferative cells, such as activated immunecells and cells transformed to make a tumor, mainly use glycolysis. Little is knownabout how individual cell types generate energy in vivo, however, and how theirmetabolism influences basic cell fate decisions such as cell division, migration ordifferentiation. Using genetically engineered mouse models that allow the study of both tissuehomeostasis and the Warburg Effect in vivo, I have made important observations thatprovide the basis for new investigations into the role of metabolism in key cell fatedecisions by adult stem cells. In this dissertation I present data indicating that hair folliclestem cells possess a unique metabolic profile that may be critical for their maintenanceand for their response to oncogenic insults. Importantly, they suggest the possibility thatthe “Warburg Effect” is the result of the expansion of an already glycolytic subpopulation,namely the hair follicle stem cells. |
