Extracellular serine controls epidermal stem cell fate and tumour initiation Journal Article
| 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. |
| Article Title: | Extracellular serine controls epidermal stem cell fate and tumour initiation |
| 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. © 2020, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | adult; controlled study; young adult; squamous cell carcinoma; nonhuman; neoplasm; animal cell; mouse; serine; animal experiment; animal model; cell fate; cell differentiation; enzyme activation; carcinogenesis; histone h3; cancer stem cell; tumor growth; glycine; nuclear reprogramming; nicotinamide adenine dinucleotide; demethylation; 2 oxoglutaric acid; histone modification; amino acid synthesis; epidermal stem cell; auxotrophy; dioxygenase; human; male; female; priority journal; article; stem cell self-renewal |
| Journal Title: | Nature Cell Biology |
| Volume: | 22 |
| Issue: | 7 |
| ISSN: | 1465-7392 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-07-01 |
| Start Page: | 779 |
| End Page: | 790 |
| Language: | English |
| DOI: | 10.1038/s41556-020-0525-9 |
| PUBMED: | 32451440 |
| PROVIDER: | scopus |
| PMCID: | PMC7343604 |
| DOI/URL: | |
| Notes: | Erratum issued, see DOI: 10.1038/s41556-020-00600-x -- Article -- Export Date: 3 August 2020 -- Source: Scopus |
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