美国加州大学Rushika M. Perera研究组揭示了PCSK9驱动胰腺癌中固醇依赖性转移器官选择。相关论文于2025年5月21日发表于国际顶尖学术期刊《自然》杂志上。

通过整合人PDAC细胞系的转移性数据、小鼠体内转移模型和基因表达相关性分析，该研究组发现PCSK9可以预测肝脏和肺部的定植。PCSK9负向调节低密度脂蛋白(LDL)-胆固醇的进口，因此PCSK9低的PDAC细胞优先定植于富含LDL的肝组织。低PCSK9肝细胞摄取的低密度脂蛋白胆固醇支持促生长mTORC1在溶酶体上的激活，并通过转化为信号氧甾醇24(S)-羟基胆固醇，重新编程微环境以释放邻近肝细胞的营养物质。相反，PCSK9含量高、渴求肺的PDAC细胞依赖于远端胆固醇合成途径的转录上调来产生中间产物- 7-脱氢胆固醇，7-脱氢去氨甾醇-具有保护作用，可防止富氧微环境中的铁凋亡。增加PCSK9的量将嗜肝细胞重定向到肺，而消融PCSK9将嗜肺细胞转移到肝脏，从而确定PCSK9是次要器官部位偏好的必要和充分条件。他们的研究表明，PCSK9驱动的远端胆固醇合成途径的差异利用是PDAC转移性生长的关键和潜在的可操作驱动因素。

据了解，为了在远处生长，转移细胞必须克服次要器官独特的细胞和代谢组成所带来的主要挑战。胰腺导管腺癌（PDAC）是一种转移到肝脏和肺部的侵袭性疾病。尽管有证据表明代谢重编程远离原发部位，但决定PDAC细胞在肝脏或肺部定植并在那里存活的能力的关键驱动因素仍未明确。

附：英文原文

Title: PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer

Author: Rademaker, Gilles, Hernandez, Grace A., Seo, Yurim, Dahal, Sumena, Miller-Phillips, Lisa, Li, Alexander L., Peng, Xianlu Laura, Luan, Changfei, Qiu, Longhui, Liegeois, Maude A., Wang, Bruce, Wen, Kwun W., Kim, Grace E., Collisson, Eric A., Kruger, Stephan F., Boeck, Stefan, Ormanns, Steffen, Guenther, Michael, Heinemann, Volker, Haas, Michael, Looney, Mark R., Yeh, Jen Jen, Zoncu, Roberto, Perera, Rushika M.

Issue&Volume: 2025-05-21

Abstract: To grow at distant sites, metastatic cells must overcome major challenges posed by the unique cellular and metabolic composition of secondary organs1. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that metastasizes to the liver and lungs. Despite evidence of metabolic reprogramming away from the primary site, the key drivers that dictate the ability of PDAC cells to colonize the liver or lungs and survive there remain undefined. Here we identified PCSK9 as predictive of liver versus lung colonization by integrating metastatic tropism data of human PDAC cell lines2, in vivo metastasis modelling in mice and gene expression correlation analysis. PCSK9 negatively regulates low density lipoprotein (LDL)-cholesterol import and, accordingly, PCSK9-low PDAC cells preferentially colonize LDL-rich liver tissue. LDL-cholesterol taken up by liver-avid PCSK9-low cells supports activation of pro-growth mTORC1 activation at the lysosome, and through conversion into the signalling oxysterol, 24(S)-hydroxycholesterol, reprogrammes the microenvironment to release nutrients from neighbouring hepatocytes. Conversely, PCSK9-high, lung-avid PDAC cells rely on transcriptional upregulation of the distal cholesterol synthesis pathway to generate intermediates—7-dehydrocholesterol and 7-dehydrodesmosterol—with protective action against ferroptosis, a vulnerability in the oxygen-rich microenvironment of the lung. Increasing the amount of PCSK9 redirected liver-avid cells to the lung whereas ablating PCSK9 drove lung-avid cells to the liver, thereby establishing PCSK9 as necessary and sufficient for secondary organ site preference. Our studies reveal PCSK9-driven differential utilization of the distal cholesterol synthesis pathway as a key and potentially actionable driver of metastatic growth in PDAC.

DOI: 10.1038/s41586-025-09017-8

Source: https://www.nature.com/articles/s41586-025-09017-8