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 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

83 Scopus citations

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 (US)
Pages (from-to)875-888.e20
JournalCell
Volume170
Issue number5
DOIs
StatePublished - Aug 24 2017

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Keywords

  • enhancer
  • FOXA1
  • metastasis
  • organoid
  • pancreatic cancer
  • pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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., 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