Student Theses and Dissertations
Date of Award
2021
Document Type
Thesis
Degree Name
Doctor of Philosophy (PhD)
Thesis Advisor
Elaine Fuchs
Keywords
epidermal stem cells, serine metabolism, stem cell fate, alpha-ketoglutarate, tumor initiation, wound repair
Abstract
Tissue stem cells balance fate decisions of self-renewal and differentiation to maintain homeostasis over the lifetime of an organism, as well as to repair tissues upon injury and wounding. Disrupting the balance between self-renewal and differentiation results in pathology: excessive self-renewal at the expense of differentiation is associated with tumor initiation, whereas failure to properly self-renew leads to stem cell exhaustion and aging. Stem cell fate is under tight regulation by the surrounding microenvironment, or niche, which includes neighboring cell types, signaling molecules, extracellular matrix, and nutrients. While the role of stromal cells and the signals they produce has been extensively studied with regards to control of stem cell fate, relatively little known is about how tissue stem cells integrate extracellular nutrient availability with fate decisions. Moreover, while intracellular metabolic pathways have been shown to regulate the balance of self-renewal and differentiation, it remains unknown whether or not endogenous metabolic pathways or nutrient availability predispose stem cells towards transformation or control their responses to tissue injury. Here, I address these questions in epidermal stem cells (EpdSCs), which maintain integrity of the skin barrier over an organism's life. EpdSCs are a cell of origin for squamous cell carcinomas (SCCs), amongst the most common and threatening malignancies worldwide. Additionally, EpdSCs of the interfollicular epidermis (IFE) and hair follicle (HF) respond to injuries in the skin barrier to repair the breach. First focusing on tumor initiation, I find oncogenic EpdSCs are serine auxotrophs, whose growth and self-renewal require abundant exogenous serine. When extracellular serine is limited in vitro and in vivo, EpdSCs activate de novo serine synthesis, which in turn produces the metabolite α-ketoglutarate (αKG). αKG stimulates terminal differentiation via activation of αKG-dependent dioxygenases that remove the repressive histone modification H3K27me3, which otherwise promotes EpdSC self-renewal. Accordingly, serine starvation or enforced αKG production antagonizes SCC initiation and growth. Conversely, blocking serine synthesis or repressing αKG-driven demethylation facilitates malignant progression in vivo. Finally, I extend these findings to stem cell responses to tissue injury. In the epidermis, abrasion of the IFE activates HFSCs to repair the breach, which is associated with transient hyperproliferation, migration and activation of a plasticity program termed lineage infidelity wherein HFSCs undergo a fate switch to become IFE-SCs, fueling regeneration of a non-cognate tissue. I find that environmental serine restriction accelerates HFSC-mediated wound repair, which I link specifically to acceleration of stem cell plasticity and acquisition of IFE fate. Altogether, these findings reveal that extracellular serine is a critical determinant of EpdSC fate and provide insight into how nutrient availability is integrated with stem cell fate decisions during tumor initiation and tissue repair.
License and Reuse Information
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Baksh, Sanjeethan C., "Metabolic Coordination of Stem Cell Fate Controls Tumor Initiation and Tissue Repair" (2021). Student Theses and Dissertations. 606.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/606
Comments
A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy