5 years ago

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis
Youngkyu Park, Richard A. Burkhart, David A. Tuveson, Paul M. Grandgenett, Michael A. Hollingsworth, James A. Grunkemeyer, Brianna Creighton, Dea Filippini, Jae-Seok Roe, Audrey J. Lazenby, Chang-Il Hwang, Christopher R. Vakoc, Joseph P. Milazzo, Jonathan M. Buscaglia, Koji Miyabayashi, C. Megan Young, Hervé Tiriac, Mikala Egeblad, Laura Maiorino, Brandon Da Silva, Tim D.D. Somerville, Jean L. Grem, Edward J. Kim, Eun Jung Lee


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.

Publisher URL: http://www.cell.com/cell/fulltext/S0092-8674(17)30814-0

DOI: 10.1016/j.cell.2017.07.007

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