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Cell. 2017 Aug 24;170(5):875-888.e20. doi: 10.1016/j.cell.2017.07.007. Epub 2017 Jul 27.

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis.

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
3
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, MD 21287, USA.
4
Division of Gastroenterology & Hepatology, Stony Brook University School of Medicine, Stony Brook, NY 11790, USA.
5
Division of Hematology/Oncology, UC Davis Medical Center, Sacramento, CA 95817, USA.
6
Department of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
7
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
8
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
9
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: dtuveson@cshl.edu.
10
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: vakoc@cshl.edu.

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.

KEYWORDS:

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

PMID:
28757253
PMCID:
PMC5726277
DOI:
10.1016/j.cell.2017.07.007
[Indexed for MEDLINE]
Free PMC Article

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