Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

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

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)875-888.e20
JournalCell
Volume170
Issue number5
DOIs
Publication statusPublished - 2017 Aug 24

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Roe, J. S., Hwang, C. I., Somerville, T. D. D., Milazzo, J. P., Lee, E. J., Da Silva, B., Maiorino, L., Tiriac, H., Young, C. M., Miyabayashi, K., Filippini, D., Creighton, B., Burkhart, R. A., Buscaglia, J. M., Kim, E. J., Grem, J. L., Lazenby, A. J., Grunkemeyer, J. A., Hollingsworth, M. A., ... Vakoc, C. R. (2017). Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. Cell, 170(5), 875-888.e20. https://doi.org/10.1016/j.cell.2017.07.007