The Role Of Metabolism In Stem Cell Fates PDF Download

For an increasing number of cancers, the cell of origin has been demonstrated to be the resident adult stem cell. One such cancer is squamous cell carcinoma, for which recent studies in our lab traced its origin to the hair follicle stem cells. Malignant transformation is thought to coincide with a dramatic shift towards the use of glycolysis and establishment of a 'Warburg' state - increased metabolism of glucose to lactate. How the Warburg Effect is established during tumor initiation and progression in vivo remains unclear. The current consensus is that the bulk of the energy generated in most adult tissue cells is created by oxidative phosphorylation, while more highly proliferative cells, such as activated immune cells and cells transformed to make a tumor, mainly use glycolysis. Little is known about how individual cell types generate energy in vivo, however, and how their metabolism influences basic cell fate decisions such as cell division, migration or differentiation. Using genetically engineered mouse models that allow the study of both tissue homeostasis and the Warburg Effect in vivo, I have made important observations that provide the basis for new investigations into the role of metabolism in key cell fate decisions by adult stem cells. In this dissertation I present data indicating that hair follicle stem cells possess a unique metabolic profile that may be critical for their maintenance and for their response to oncogenic insults. Importantly, they suggest the possibility that the "Warburg Effect" is the result of the expansion of an already glycolytic subpopulation, namely the hair follicle stem cells.