Genome binding/occupancy profiling by high throughput sequencing
Summary
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 each stage of PDA progression. This approach revealed that the metastatic transition is accompanied by massive, and recurrent alterations in enhancer activity. We implicate the transcription factors FOXA1 and GATA5 as drivers of enhancer activation in this system, a mechanism that we show renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. FOXA1 and GATA5 were found to activate a foregut endoderm transcriptional program in PDA cells, without altering genes associated with the epithelial-to- mesenchymal transition. Collectively, our study implicates FOXA1/GATA5 upregulation, enhancer reprogramming, and a novel retrograde developmental transition in PDA progression and metastasis.
Overall design
H3K27ac, H3K4me1, Foxa1 ChIP-Seq of mouse and/or human PDA organoids and/or cell lines
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