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 | |
| State | Published - 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
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
}
TY - JOUR
T1 - Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis
AU - Roe, Jae Seok
AU - Hwang, Chang Il
AU - Somerville, Tim D.D.
AU - Milazzo, Joseph P.
AU - Lee, Eun Jung
AU - Da Silva, Brandon
AU - Maiorino, Laura
AU - Tiriac, Hervé
AU - Young, C. Megan
AU - Miyabayashi, Koji
AU - Filippini, Dea
AU - Creighton, Brianna
AU - Burkhart, Richard A.
AU - Buscaglia, Jonathan M.
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.
PY - 2017/8/24
Y1 - 2017/8/24
N2 - 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.
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.
KW - enhancer
KW - FOXA1
KW - metastasis
KW - organoid
KW - pancreatic cancer
KW - pancreatic ductal adenocarcinoma
UR - http://www.scopus.com/inward/record.url?scp=85026197846&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026197846&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2017.07.007
DO - 10.1016/j.cell.2017.07.007
M3 - Article
C2 - 28757253
AN - SCOPUS:85026197846
VL - 170
SP - 875-888.e20
JO - Cell
JF - Cell
SN - 0092-8674
IS - 5
ER -