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.

SIGNIFICANCE: 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. Cancer Discov; 7(10); 1–16. ©2017 AACR.

See related commentary by Vakoc and Tuveson, p. 1067.

胰腺导管腺癌（PDAC）是最转移和致命的癌症之一。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了解仍然有限。通过生成人类PDAC的基因工程小鼠模型，我们发现了具有极高转移能力的癌细胞的瞬时亚群。全局基因表达谱和功能分析发现转录因子BLIMP1作为PDAC转移的驱动器。高转移性PDAC亚群富含低氧诱导的基因，而低氧介导的BLIMP1诱导则有助于调节与低氧相关的基因表达程序的子集。

意义： PDAC是一种几乎一致的致死性癌症，主要是由于其转移的趋势。我们定义了癌细胞的高度转移亚群，揭示了转移能力的关键转录调节因子，并将缺氧定义为肿瘤微环境中增加转移倾向的重要因素。巨蟹座Discov; 7（10）；1–16。©2017 AACR。

参见Vakoc和Tuveson，p。的相关评论。1067。