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.

组织干细胞是许多恶性肿瘤的起源细胞。代谢物调节自我更新和分化之间的平衡，但内源性代谢途径或营养供应是否使干细胞易于转化仍然未知。在这里，我们在表皮干细胞 (EpdSCs) 中解决了这个问题，EpdSCs 是鳞状细胞癌的起源细胞。我们发现致癌的 EpdSCs 是丝氨酸营养缺陷型，其生长和自我更新需要丰富的外源丝氨酸。当细胞外丝氨酸受到限制时，EpdSCs 激活从头丝氨酸合成，进而刺激 α-酮戊二酸依赖性双加氧酶，去除抑制性组蛋白修饰 H3K27me3 并激活分化程序。因此，丝氨酸饥饿或强制产生 α-酮戊二酸可拮抗鳞状细胞癌的生长。相反，阻断丝氨酸合成或抑制α-酮戊二酸驱动的去甲基化会促进恶性进展。总之，这些研究结果表明，细胞外丝氨酸是 EpdSC 命运的关键决定因素，并提供了对肿瘤起始过程中营养可用性如何与干细胞命运决定相结合的见解。