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. Grandgenett; Mikala Egeblad; Youngkyu Park; David A. Tuveson; Christopher R. Vakoc

doi:10.1016/j.cell.2017.07.007

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

Hematology and Oncology

Research output: Contribution to journal › Article

106 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 language	English (US)
Pages (from-to)	875-888.e20
Journal	Cell
Volume	170
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2017.07.007
State	Published - Aug 24 2017

Keywords

enhancer
FOXA1
metastasis
organoid
pancreatic cancer
pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2017.07.007

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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., 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

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; 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 journal › Article

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, E, 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, 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 ; 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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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.",

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AU - Da Silva, Brandon

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AU - Kim, Edward

AU - Grem, Jean L.

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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AB - 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.

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