Extracellular serine controls epidermal stem cell fate and tumour initiation
- 24 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 22 (7), 779-790
- https://doi.org/10.1038/s41556-020-0525-9
Abstract
Tissue stem cells are the cell of origin for many malignancies. Metabolites regulate the balance between self-renewal and differentiation, but whether endogenous metabolic pathways or nutrient availability predispose stem cells towards transformation remains unknown. Here, we address this question in epidermal stem cells (EpdSCs), which are a cell of origin for squamous cell carcinoma. We find that oncogenic EpdSCs are serine auxotrophs whose growth and self-renewal require abundant exogenous serine. When extracellular serine is limited, EpdSCs activate de novo serine synthesis, which in turn stimulates α-ketoglutarate-dependent dioxygenases that remove the repressive histone modification H3K27me3 and activate differentiation programmes. Accordingly, serine starvation or enforced α-ketoglutarate production antagonizes squamous cell carcinoma growth. Conversely, blocking serine synthesis or repressing α-ketoglutarate-driven demethylation facilitates malignant progression. Together, 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 tumour initiation.Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (F31CA236465, 1F32AR073105, R01-AR31737)
- Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional Medical Scientist Training Program
- European Molecular Biology Organization (ALTF 1239- 2016)
- Human Frontier Science Program (LT001519/2017)
- Foundation for the National Institutes of Health (F30CA236239-01)
- New York State Stem Cell Science (CO29559)
- Starr Foundation (I11-0039, I11-0039, I12-051)
- Howard Hughes Medical Institute
- Damon Runyon Cancer Research Foundation (DFS-23-17)
- Searle Scholars, Anna Fuller Fund, Concern Foundation, Edward Mallinckrodt, Jr. Foundation
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