Extracellular serine controls epidermal stem cell fate and tumor initiation

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 to transformation remains unknown. Here, we address this question in epidermal stem cells (EpdSCs), a cell of origin for squamous cell carcinoma (SCC). We find that oncogenic EpdSCs are serine auxotrophs whose growth and self-renewal requires abundant exogenous serine. When extracellular serine is limiting, EpdSCs activate de novo serine synthesis, which in turn stimulates αKG-dependent dioxygenases that remove the repressive histone modification H3K27me3 and activate differentiation programs. Accordingly, serine starvation or enforced α-ketoglutarate production antagonizes SCC 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 tumor initiation.