Department of Genetics, Stanford University School of Medicine, Stanford, California.
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California.
Cancer Discov. 2017 Oct;7(10):1184-1199. doi: 10.1158/2159-8290.CD-17-0250. Epub 2017 Aug 8.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most metastatic and deadly cancers. Despite the clinical significance of metastatic spread, our understanding of molecular mechanisms that drive PDAC metastatic ability remains limited. By generating a genetically engineered mouse model of human PDAC, we uncover a transient subpopulation of cancer cells with exceptionally high metastatic ability. Global gene expression profiling and functional analyses uncovered the transcription factor BLIMP1 as a driver of PDAC metastasis. The highly metastatic PDAC subpopulation is enriched for hypoxia-induced genes, and hypoxia-mediated induction of BLIMP1 contributes to the regulation of a subset of hypoxia-associated gene expression programs. These findings support a model in which upregulation of BLIMP1 links microenvironmental cues to a metastatic stem cell character. PDAC is an almost uniformly lethal cancer, largely due to its tendency for metastasis. We define a highly metastatic subpopulation of cancer cells, uncover a key transcriptional regulator of metastatic ability, and define hypoxia as an important factor within the tumor microenvironment that increases metastatic proclivity. .
胰腺导管腺癌（PDAC）是最具转移性和致命性的癌症之一。尽管转移扩散具有临床意义，但我们对驱动 PDAC 转移能力的分子机制的理解仍然有限。通过生成人类 PDAC 的基因工程小鼠模型，我们发现了具有异常高转移能力的癌细胞短暂亚群。全基因表达谱分析和功能分析揭示了转录因子 BLIMP1 是 PDAC 转移的驱动因素。高度转移性的 PDAC 亚群富含缺氧诱导基因，而缺氧介导的 BLIMP1 诱导有助于调节一组与缺氧相关的基因表达程序。这些发现支持了这样一种模型，即 BLIMP1 的上调将微环境线索与转移性干细胞特征联系起来。PDAC 是一种几乎普遍致命的癌症，主要是由于其转移倾向。我们定义了一个具有高转移性的癌细胞亚群，揭示了转移性能力的关键转录调节因子，并将缺氧定义为肿瘤微环境中的一个重要因素，增加了转移倾向。
