Lv Yajing, Wang Xiaoshuang, Li Xiaoyu, Xu Guangwei, Bai Yuting, Wu Jiayi, Piao Yongjun, Shi Yi, Xiang Rong, Wang Longlong
School of Medicine, Nankai University, Tianjin, China.
Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
PLoS Biol. 2020 Nov 13;18(11):e3000872. doi: 10.1371/journal.pbio.3000872. eCollection 2020 Nov.
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，代谢重编程以满足癌细胞的生物合成和生物能量需求引起了极大关注。然而，关于癌症转移的代谢重编程尚未得到充分阐明。在此，我们筛选出了在小鼠中对肺具有高转移能力的乳腺癌细胞亚群，并通过分析代谢组和转录组来研究代谢变化，这些变化在乳腺癌细胞、小鼠模型和患者组织中得到了证实。我们还在体外和体内进一步评估了核苷酸从头合成在癌症转移中的作用及机制。在我们的研究中，我们报告了核苷酸从头合成增加是转移性乳腺癌细胞的关键代谢特征，并揭示强制进行核苷酸从头合成足以驱动乳腺癌细胞的转移。从头合成的关键代谢产物鸟苷 - 5'-三磷酸（GTP）增加，能够产生更多的环磷酸鸟苷（cGMP）以激活cGMP依赖性蛋白激酶PKG和下游的丝裂原活化蛋白激酶（MAPK）途径，从而导致肿瘤细胞干性和转移增加。通过沉默磷酸核糖焦磷酸合成酶2（PRPS2）来阻断从头合成可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，嘌呤的下游代谢产物血浆尿酸（UA）水平与患者的生存率密切相关。我们的研究发现，从头合成增加是转移性乳腺癌细胞的代谢特征，其代谢产物可调节信号通路以促进乳腺癌的干性和转移。
