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: | |
| 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: | |
| URI: | https://repository.cshl.edu/id/eprint/35083 |
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