UCLA

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.