肝细胞通过提供丝氨酸促进胰腺癌肝转移
Hepatocytes promote liver metastasis of pancreatic cancer by providing serine
肝脏是胰腺导管腺癌（PDAC）最常见的转移部位，也是致死主因。约 40% 的 PDAC 缺失 PHGDH（丝氨酸合成限速酶），必须依赖外源丝氨酸，但它们如何在肝脏微环境生长尚不清楚。研究发现，依赖外源丝氨酸的 PDAC 细胞通过 CXCL5-CXCR2 轴重编程邻近肝细胞，激活 PI3K-AKT 通路，使 FOXO3A 滞留胞质、解除对 PHGDH 转录的抑制，从而增强肝细胞产丝氨酸。肝细胞来源的丝氨酸支持转移灶生长；阻断该轴或肝细胞特异性敲除 Phgdh/Cxcr2 可显著减轻小鼠肝转移并延长生存，尤其当饮食限制丝氨酸时。这揭示了癌细胞-肝细胞的代谢对话及潜在治疗靶点。
为什么推荐给您：揭示肿瘤-肝细胞代谢交互新机制并提出可干预靶点，属重要新机制。
不需要生物学背景，多打比方
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摘要Abstract
The liver is the primary site of metastasis in pancreatic ductal adenocarcinoma (PDAC), and liver metastases are a major cause of mortality1,2. Nutrient availability in the metastatic niche influences colonization efficiency; however, the metabolic heterogeneity of disseminated tumour cells can also reshape the local microenvironment3-5. Loss of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine biosynthesis, is observed in nearly 40% of PDACs, and renders these cells dependent on exogenous serine (exSer)6. Although a neuron-tumour metabolic cross-talk supports exSer-dependent PDAC cells at the primary site6, it remains unclear how these cells adapt to the metastatic liver niche. Here we show that exSer-dependent PDAC cells reprogram neighbouring hepatocytes through a CXCL5-CXCR2 axis. Activation of CXCR2 in hepatocytes promotes PI3K-AKT signalling, leading to the sequestration of FOXO3A in the cytoplasm and derepression of PHGDH transcription, thereby enhancing serine production in hepatocytes. This hepatocyte-derived serine supports the outgrowth of exSer-dependent PDAC liver metastases. Accordingly, genetic or pharmacological inhibition of individual nodes within the CXCL5-CXCR2-PI3K-AKT-FOXO3A axis, or hepatocyte-specific deletion of Phgdh or Cxcr2, markedly reduces the liver-metastasis burden in mice and prolongs survival, particularly when dietary serine is restricted. Our findings reveal a cancer cell-hepatocyte metabolic cross-talk and identify therapeutic targets for exSer-dependent PDAC liver metastases.