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. (August 2017) Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. Cell, 170 (5). pp. 875-888. ISSN 0092-8674

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:	Roe, Jae Seok Hwang, Chang-Il Somerville, Timothy Milazzo, Joseph Lee, Eunjung Da Silva, Brandon Maiorino, Laura Tiriac, Herve Filippini, Dea Creighton, Brianna Egeblad, Mikala Park, Youngkyu Tuveson, David A. Vakoc, Christopher R. Young, Candice Megan Miyabayashi, Koji
Communities:	CSHL Cancer Center Program > Gene Regulation and Cell Proliferation CSHL Cancer Center Program > Signal Transduction CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL labs > Egeblad lab CSHL labs > Tuveson lab CSHL labs > Vakoc lab School of Biological Sciences > Publications CSHL Cancer Center Shared Resources > Animal Shared Resource
Depositing User:	Matt Covey
Date:	24 August 2017
Date Deposited:	04 Aug 2017 19:46
Last Modified:	15 Nov 2023 18:19
PMCID:	PMC5726277
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/35083

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