癌症中有三分之一会启动内源性合成丝氨酸/甘氨酸，并会成瘾于该途径以维持增殖和存活。驱动这种代谢重构的机制基本未知。建立了过表达NKX2-1和NKX2-1敲除/敲减T细胞白血病和肺癌细胞系的模型，通过ChIP-qPCR、免疫印迹、质谱和增殖和侵袭实验研究代谢重构。在小鼠模型和患者数据集中验证了发现和治疗相关性。探索T细胞白血病、肺癌和神经内分泌前列腺癌患者的数据集，突出了转录因子NKX2-1作为丝氨酸/甘氨酸代谢的潜在驱动因子。我们证明，转录因子NKX2-1结合并上调丝氨酸/甘氨酸合成酶基因，使NKX2-1表达细胞能够在缺乏丝氨酸/甘氨酸的条件下增殖和入侵。NKX2-1驱动的丝氨酸/甘氨酸合成产生核苷酸和还原分子，并与改变的细胞脂质组和甲基组相关。因此，NKX2-1肿瘤携带的小鼠显示出增强的肿瘤侵袭性，伴随着全身代谢重构。从治疗学角度来看，NKX2-1表达的癌细胞对盐酸西酞普兰转化抑制剂和依托泊苷化疗更加敏感。综上所述，我们确定了NKX2-1作为癌症中丝氨酸/甘氨酸合成成瘾的新型转录调控因子，揭示了NKX2-1驱动的癌症的治疗易感性。转录因子NKX2-1通过高度活化丝氨酸/甘氨酸合成来促进癌细胞增殖和存活，突出了该途径作为NKX2-1阳性癌症的新型治疗靶点。©2023年。作者。

One-third of cancers activate endogenous synthesis of serine/glycine, and can become addicted to this pathway to sustain proliferation and survival. Mechanisms driving this metabolic rewiring remain largely unknown.NKX2-1 overexpressing and NKX2-1 knockdown/knockout T-cell leukaemia and lung cancer cell line models were established to study metabolic rewiring using ChIP-qPCR, immunoblotting, mass spectrometry, and proliferation and invasion assays. Findings and therapeutic relevance were validated in mouse models and confirmed in patient datasets.Exploring T-cell leukaemia, lung cancer and neuroendocrine prostate cancer patient datasets highlighted the transcription factor NKX2-1 as putative driver of serine/glycine metabolism. We demonstrate that transcription factor NKX2-1 binds and transcriptionally upregulates serine/glycine synthesis enzyme genes, enabling NKX2-1 expressing cells to proliferate and invade in serine/glycine-depleted conditions. NKX2-1 driven serine/glycine synthesis generates nucleotides and redox molecules, and is associated with an altered cellular lipidome and methylome. Accordingly, NKX2-1 tumour-bearing mice display enhanced tumour aggressiveness associated with systemic metabolic rewiring. Therapeutically, NKX2-1-expressing cancer cells are more sensitive to serine/glycine conversion inhibition by repurposed anti-depressant sertraline, and to etoposide chemotherapy.Collectively, we identify NKX2-1 as a novel transcriptional regulator of serine/glycine synthesis addiction across cancers, revealing a therapeutic vulnerability of NKX2-1-driven cancers. Transcription factor NKX2-1 fuels cancer cell proliferation and survival by hyperactivating serine/glycine synthesis, highlighting this pathway as a novel therapeutic target in NKX2-1-positive cancers.© 2023. The Author(s).