Cancer cells craftily adapt their energy metabolism to their microenvironment. Nutrient deprivation due to hypovascularity and fibrosis is a major characteristic of pancreatic ductal adenocarcinoma (PDAC); thus, PDAC cells must produce energy intrinsically. However, the enhancement of energy production via activating Kras mutations is insufficient to explain the metabolic rewiring of PDAC cells. Here, we investigated the molecular mechanism underlying the metabolic shift in PDAC cells under serine starvation. Amino acid analysis revealed that the concentrations of all essential amino acids and most nonessential amino acids were decreased in the blood of PDAC patients. In addition, the plasma serine concentration was significantly higher in PDAC patients with PHGDH-high tumors than in those with PHGDH-low tumors. Although the growth and tumorigenesis of PK-59 cells with PHGDH promoter hypermethylation were significantly decreased by serine starvation, these activities were maintained in PDAC cell lines with PHGDH promoter hypomethylation by serine biosynthesis through PHGDH induction. In fact, DNA methylation analysis by pyrosequencing revealed that the methylation status of the PHGDH promoter was inversely correlated with the PHGDH expression level in human PDAC tissues. In addition to PHGDH induction by serine starvation, PDAC cells showed enhanced serine biosynthesis under serine starvation through 3-PG accumulation via PGAM1 knockdown, resulting in enhanced PDAC cell growth and tumor growth. However, PHGDH knockdown efficiently suppressed PDAC cell growth and tumor growth under serine starvation. These findings provide evidence that targeting the serine biosynthesis pathway by inhibiting PHGDH is a potent therapeutic approach to eliminate PDAC cells in nutrient-deprived microenvironments.

癌细胞巧妙地使其能量代谢适应其微环境。由于血管不足和纤维化导致的营养缺乏是胰腺导管腺癌 (PDAC) 的主要特征。因此，PDAC 细胞必须在本质上产生能量。然而，通过激活 Kras 突变来增强能量产生不足以解释 PDAC 细胞的代谢重新布线。在这里，我们研究了丝氨酸饥饿下 PDAC 细胞代谢转变的分子机制。氨基酸分析显示，PDAC 患者血液中所有必需氨基酸和大多数非必需氨基酸的浓度均降低。此外，PHGDH 高肿瘤的 PDAC 患者的血浆丝氨酸浓度显着高于 PHGDH 低肿瘤的患者。尽管丝氨酸饥饿显着降低了具有 PHGDH 启动子高甲基化的 PK-59 细胞的生长和肿瘤发生，但这些活性在 PDAC 细胞系中通过 PHGDH 诱导的丝氨酸生物合成得以维持。事实上，通过焦磷酸测序进行的 DNA 甲基化分析表明，PHGDH 启动子的甲基化状态与人 PDAC 组织中 PHGDH 的表达水平呈负相关。除了丝氨酸饥饿诱导 PHGDH 外，PDAC 细胞在丝氨酸饥饿下通过 PGAM1 敲低的 3-PG 积累显示出增强的丝氨酸生物合成，导致 PDAC 细胞生长和肿瘤生长增强。然而，PHGDH 敲低有效地抑制了丝氨酸饥饿下的 PDAC 细胞生长和肿瘤生长。