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

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

Fingerprint

Transcription
Pancreatic Neoplasms
Adenocarcinoma
Chemical activation
Neoplasm Metastasis
Organoids
Endoderm
Disease Progression
Up-Regulation
Growth
Neoplasms

Keywords

  • FOXA1
  • enhancer
  • 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., ... 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

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. / 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.

In: Cell, Vol. 170, No. 5, 24.08.2017, p. 875-888.e20.

Research output: Contribution to journalArticle

Roe, JS, Hwang, CI, Somerville, TDD, Milazzo, JP, Lee, EJ, Da Silva, B, Maiorino, L, Tiriac, H, Young, CM, Miyabayashi, K, Filippini, D, Creighton, B, Burkhart, RA, Buscaglia, JM, Kim, EJ, Grem, JL, Lazenby, AJ, Grunkemeyer, JA, Hollingsworth, MA, Grandgenett, PM, Egeblad, M, Park, Y, Tuveson, DA & Vakoc, CR 2017, 'Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis', Cell, vol. 170, no. 5, pp. 875-888.e20. https://doi.org/10.1016/j.cell.2017.07.007
Roe JS, Hwang CI, Somerville TDD, Milazzo JP, Lee EJ, Da Silva B et al. Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. Cell. 2017 Aug 24;170(5):875-888.e20. https://doi.org/10.1016/j.cell.2017.07.007
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. / Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. In: Cell. 2017 ; Vol. 170, No. 5. pp. 875-888.e20.
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AU - Lazenby, Audrey J

AU - Grunkemeyer, James A.

AU - Hollingsworth, Michael A

AU - Grandgenett, Paul M.

AU - Egeblad, Mikala

AU - Park, Youngkyu

AU - Tuveson, David A.

AU - Vakoc, Christopher R.

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