Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, China.
Nat Cancer. 2022 Aug;3(8):945-960. doi: 10.1038/s43018-022-00426-6. Epub 2022 Aug 18.
Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical for survival from pancreatic ductal adenocarcinoma (PDAC) on glutamine deprivation. Specifically, we uncovered a role for nucleosides, which are secreted by CAFs through autophagy in a nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-dependent manner, increased glucose utilization and promoted growth of PDAC. Moreover, we demonstrate that CAF-derived nucleosides induced glucose consumption under glutamine-deprived conditions and displayed a dependence on MYC. Using an orthotopic mouse model of PDAC, we found that inhibiting nucleoside secretion by targeting NUFIP1 in the stroma reduced tumor weight. This finding highlights a previously unappreciated metabolic network within pancreatic tumors in which diverse nutrients are used to promote growth in an austere tumor microenvironment.
癌症相关成纤维细胞（CAFs）是胰腺肿瘤微环境中最显著和最活跃的成分之一。我们的数据表明，CAFs 在谷氨酰胺剥夺时对胰腺导管腺癌（PDAC）的存活至关重要。具体来说，我们揭示了核脆性 X 智力低下相互作用蛋白 1（NUFIP1）依赖性自噬通过 CAFs 分泌的核苷的作用，增加葡萄糖利用并促进 PDAC 的生长。此外，我们证明 CAF 衍生的核苷在谷氨酰胺剥夺条件下诱导葡萄糖消耗，并依赖 MYC。使用 PDAC 的原位小鼠模型，我们发现通过靶向基质中的 NUFIP1 抑制核苷分泌可减少肿瘤重量。这一发现突出了胰腺肿瘤中以前未被认识的代谢网络，其中各种营养物质被用于在严峻的肿瘤微环境中促进生长。
