Roe Jae-Seok, Hwang Chang-Il, Somerville Tim D D, Milazzo Joseph P, Lee Eun Jung, Da Silva Brandon, Maiorino Laura, Tiriac Hervé, Young C Megan, Miyabayashi Koji, Filippini Dea, Creighton Brianna, Burkhart Richard A, Buscaglia Jonathan M, Kim Edward J, Grem Jean L, Lazenby Audrey J, Grunkemeyer James A, Hollingsworth Michael A, Grandgenett Paul M, Egeblad Mikala, Park Youngkyu, Tuveson David A, Vakoc Christopher R
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
Cell. 2017 Aug 24;170(5):875-888.e20. doi: 10.1016/j.cell.2017.07.007. Epub 2017 Jul 27.
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis.
胰腺导管腺癌（PDA）是最致命的人类恶性肿瘤之一，部分原因在于其转移倾向。在此，我们使用类器官培养系统来研究在PDA小鼠模型疾病进展的不同阶段转录和增强子景观是如何改变的。这种方法揭示了转移转变伴随着增强子活性的大量反复改变。我们认为先驱因子FOXA1是该系统中增强子激活的驱动因素，这一机制使PDA细胞在体外更具侵袭性且对生长的锚定依赖性更低，在体内也更具转移性。在这种情况下，FOXA1依赖的增强子重编程激活了胚胎前肠内胚层的转录程序。总体而言，我们的研究表明增强子重编程、FOXA1上调以及逆行发育转变与PDA转移有关。
