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.
Bibliographical noteFunding Information:
We would like to thank all members of the C.R.V. and D.A.T. laboratories for helpful discussions and suggestions throughout the course of this study. The authors would like to thank the Cold Spring Harbor Cancer Center Support Grant (CCSG, P30CA045508-29) shared resources: Bioinformatics Shared Resource, Microscope, DNA Sequencing, Animal & Tissue Imaging, and the Animal Facility. We are grateful to Junichi Takagi at Osaka University for sharing the Afamin/Wnt3A cell line. This project was also funded by NCI 5P01CA013106-Project 4 (C.R.V.), a Career Development Award from the Pancreatic Cancer Action Network-AACR 16-20-25-VAKO (C.R.V.), and the Lustgarten Foundation, where D.A.T. is a distinguished scholar and Director of the Lustgarten Foundation?designated Laboratory of Pancreatic Cancer Research. D.A.T. is also supported by the Cold Spring Harbor Laboratory Association, the National Institutes of Health (NIH; 5P30CA45508-29, 5P50CA101955-07, 1U10CA180944-04, 5U01CA168409-5, 1R01CA188134-01, and 1R01CA190092-04), and the V Foundation. In addition, we are grateful for support from the following: Stand Up to Cancer/AACR PS09 (D.A.T.), NCI (1F32CA180717-01A1 for C.-I.H. and P50CA127297 for P.M.G, M.A.H., J.L.G., A.J.L., and J.A.G), Daiichi Sankyo Foundation of Life Science fellowship and Uehara Memorial Foundation research fellowship (K.M.), Stony Brook pilot project grant (J.M.B.), ASGE (J.M.B.), SWOG ITSC 5U10CA180944-04 (E.J.K, D.A.T., H.T.), and NIH (R50CA211506-01 for Y.P., P20CA19299402 for J.M.B. and D.A.T., and 5T32CA126607-08 for R.A.B.).
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)