Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

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. J., Grem, J. L., Lazenby, A. J., Grunkemeyer, J. A., Hollingsworth, M. A., Grandgenett, P. M., Egeblad, M., Park, Y., Tuveson, D. A., Vakoc, C. R. (2017) Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. Cell, 170 (5). pp. 875-888. ISSN 0092-8674

URL: https://www.ncbi.nlm.nih.gov/pubmed/28757253
DOI: 10.1016/j.cell.2017.07.007

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.

Item Type: Paper
Uncontrolled Keywords: Foxa1 enhancer metastasis organoid pancreatic cancer pancreatic ductal adenocarcinoma
Subjects: diseases & disorders > cancer > metastasis
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Egeblad lab
CSHL labs > Tuveson lab
CSHL labs > Vakoc lab
Depositing User: Matt Covey
Date Deposited: 04 Aug 2017 19:46
Last Modified: 07 Sep 2017 20:15
Related URLs:
URI: http://repository.cshl.edu/id/eprint/35083

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