Metabolic reprogramming to fulfill the biosynthetic and bioenergetic demands of cancer cells has aroused great interest in recent years. However, metabolic reprogramming for cancer metastasis has not been well elucidated. Here, we screened a subpopulation of breast cancer cells with highly metastatic capacity to the lung in mice and investigated the metabolic alternations by analyzing the metabolome and the transcriptome, which were confirmed in breast cancer cells, mouse models, and patients’ tissues. The effects and the mechanisms of nucleotide de novo synthesis in cancer metastasis were further evaluated in vitro and in vivo. In our study, we report an increased nucleotide de novo synthesis as a key metabolic hallmark in metastatic breast cancer cells and revealed that enforced nucleotide de novo synthesis was enough to drive the metastasis of breast cancer cells. An increased key metabolite of de novo synthesis, guanosine-5'-triphosphate (GTP), is able to generate more cyclic guanosine monophosphate (cGMP) to activate cGMP-dependent protein kinases PKG and downstream MAPK pathway, resulting in the increased tumor cell stemness and metastasis. Blocking de novo synthesis by silencing phosphoribosylpyrophosphate synthetase 2 (PRPS2) can effectively decrease the stemness of breast cancer cells and reduce the lung metastasis. More interestingly, in breast cancer patients, the level of plasma uric acid (UA), a downstream metabolite of purine, is tightly correlated with patient’s survival. Our study uncovered that increased de novo synthesis is a metabolic hallmark of metastatic breast cancer cells and its metabolites can regulate the signaling pathway to promote the stemness and metastasis of breast cancer.

近年来，为了满足癌细胞的生物合成和生物能需求而进行的代谢重编程引起了人们的极大兴趣。然而，尚未充分阐明用于癌症转移的代谢重编程。在这里，我们筛选了在小鼠中具有高度向肺转移能力的乳腺癌细胞亚群，并通过分析在乳腺癌细胞，小鼠模型和患者组织中证实的代谢组和转录组来研究代谢变化。体内和体外进一步评估了核苷酸从头合成在癌症转移中的作用和机制。在我们的研究中 我们报道增加的核苷酸从头合成作为转移性乳腺癌细胞中的关键代谢标志，并揭示了强制性的核苷酸从头合成足以驱动乳腺癌细胞的转移。从头合成的增加的关键代谢物鸟苷5'-三磷酸（GTP）能够产生更多的环状鸟苷单磷酸（cGMP），以激活cGMP依赖性蛋白激酶PKG和下游MAPK途径，从而导致肿瘤细胞干度增加和转移。通过使磷酸核糖焦磷酸合成酶2（PRPS2）沉默来阻止从头合成，可以有效降低乳腺癌细胞的干性并减少肺转移。更有趣的是，在乳腺癌患者中，血浆尿酸（UA）（嘌呤的下游代谢产物）的水平 与患者的生存密切相关。我们的研究发现，从头合成的增加是转移性乳腺癌细胞的代谢特征，其代谢产物可以调节信号通路，从而促进乳腺癌的干性和转移。