美国密歇根大学Costas A. Lyssiotis等研究人员合作发现，尿苷衍生的核糖为葡萄糖受限的胰腺癌提供能源。该研究于2023年5月17日在线发表于国际一流学术期刊《自然》。

通过评估超过175种代谢物如何影响21种胰腺细胞系在营养限制下的代谢活动，研究人员确定尿苷是胰腺导管腺癌（PDA）在葡萄糖匮乏条件下的一种能源。尿苷的利用与尿苷磷酸化酶1（UPP1）的表达密切相关，研究人员证明尿苷衍生的核糖为核心碳代谢提供能源，从而支持葡萄糖限制的PDA细胞的氧化还原平衡、生存和增殖。在PDA中，UPP1受KRAS-MAPK信号的调节，并因营养限制而增强。

一致的是，与非肿瘤组织相比，肿瘤的UPP1表达量很高，而且UPP1的表达与PDA患者群中的不良生存率相关联。尿苷在肿瘤微环境中是可用的，而且研究人员证明尿苷衍生的核糖在肿瘤中被主动分解。最后，UPP1的缺失限制了PDA细胞使用尿苷的能力，并在免疫功能正常的小鼠模型中减弱了肿瘤的生长。这些数据表明，尿苷的利用是营养匮乏的PDA细胞的一个重要的补偿性代谢过程，并提出PDA治疗的一个新的代谢轴。

据了解，PDA是一种致命的疾病，对治疗有明显的抵抗力。这部分是由复杂的肿瘤微环境、低血管性和代谢异常所促成。虽然新陈代谢的改变推动了肿瘤的发展，但PDA作为营养物质使用的代谢物的范围在很大程度上仍然是未知的。

附：英文原文

Title: Uridine-derived ribose fuels glucose-restricted pancreatic cancer

Author: Nwosu, Zeribe C., Ward, Matthew H., Sajjakulnukit, Peter, Poudel, Pawan, Ragulan, Chanthirika, Kasperek, Steven, Radyk, Megan, Sutton, Damien, Menjivar, Rosa E., Andren, Anthony, Apiz-Saab, Juan J., Tolstyka, Zachary, Brown, Kristee, Lee, Ho-Joon, Dzierozynski, Lindsey N., He, Xi, PS, Hari, Ugras, Julia, Nyamundanda, Gift, Zhang, Li, Halbrook, Christopher J., Carpenter, Eileen S., Shi, Jiaqi, Shriver, Leah P., Patti, Gary J., Muir, Alexander, Pasca di Magliano, Marina, Sadanandam, Anguraj, Lyssiotis, Costas A.

Issue&Volume: 2023-05-17

Abstract: Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS–MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.

DOI: 10.1038/s41586-023-06073-w

Source: https://www.nature.com/articles/s41586-023-06073-w