Extracellular serine controls epidermal stem cell fate and tumour initiation
Open accessAbstract
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.
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Electron shuttles facilitate oxidation of cytosolic NADH, which is required to support continued glycolysis and de novo synthesis of serine and lipids.
“Beyond supporting net NADH “import” into the mitochondria, these shuttles also facilitate the oxidation of cytosolic NADH, which is required to support continued glycolysis and the de novo synthesis of serine and lipids (101, 102, 103).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [101]
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References 70 · Cited by 128
- Authors
- Baksh, S. C., Todorova, P. K., Gur-Cohen, S., Hurwitz, B., Ge, Y., Novak, J. S. S., Tierney, M. T., dela Cruz-Racelis, J., Fuchs, E., & Finley, L. W. S.
- Affiliations
- Howard Hughes Medical Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Fuchs, Elaine
- Finley, Lydia W. S.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2020-05-25
- Volume
- 22
- Issue
- 7
- Pages
- 779-790
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC7343604
- OpenAlex
- W3026410170
- Cited by
- 128
- References
- 70
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 15 · 2023: 25 · 2022: 20 · 2021: 22 · 2020: 13
- FWCI
- 6.84
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-10-12)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- 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, 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
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- epidermal stem cells, squamous cell carcinoma, de novo serine synthesis, alpha-ketoglutarate, histone demethylation, H3K27me3, stem cell self-renewal, stem cell differentiation, tumor initiation, nutrient availability
- MeSH terms
- Epidermal Cells, Animals, Carcinoma, Squamous Cell, Cell Differentiation, Cell Transformation, Neoplastic, Cells, Cultured, Female, Humans, Ketoglutaric Acids, Male, Serine, Stem Cells, Mice
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