Extracellular serine controls epidermal stem cell fate and tumour initiation.
| Publication Type | Academic Article |
| Authors | Baksh S, Todorova P, Gur-Cohen S, Hurwitz B, Ge Y, Novak J, Tierney M, Dela Cruz-Racelis J, Fuchs E, Finley L |
| Journal | Nat Cell Biol |
| Volume | 22 |
| Issue | 7 |
| Pagination | 779-790 |
| Date Published | 05/25/2020 |
| ISSN | 1476-4679 |
| Keywords | Carcinoma, Squamous Cell, Cell Transformation, Neoplastic, Epidermal Cells, Ketoglutaric Acids, Serine, Stem Cells |
| 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. |
| DOI | 10.1038/s41556-020-0525-9 |
| PubMed ID | 32451440 |
| PubMed Central ID | PMC7343604 |