Open AccessExtracellular serine controls epidermal stem cell fate and tumour initiation
Author(s) -
Sanjeethan C. Baksh,
Pavlina Krasimirova Todorova,
Shiri Gur-Cohen,
Brian Hurwitz,
Yejing Ge,
Jesse Novak,
Matthew Tierney,
June dela Cruz-Racelis,
Elaine Fuchs,
Lydia W.S. Finley
Publication year - 2020
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-020-0525-9
Subject(s) - serine , extracellular , biology , cell fate determination , microbiology and biotechnology , stem cell , cellular differentiation , cell growth , biochemistry , phosphorylation , transcription factor , gene
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.