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Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis.

Cell | Aug 24, 2017

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.

Pubmed ID: 28757253 RIS Download

Mesh terms: Adenocarcinoma | Animals | Carcinoma, Pancreatic Ductal | Cell Line, Tumor | Disease Models, Animal | Enhancer Elements, Genetic | Epigenomics | Female | Gene Expression Profiling | Gene Expression Regulation, Neoplastic | Hepatocyte Nuclear Factor 3-alpha | Humans | Male | Mice | Mice, Inbred C57BL | Neoplasm Metastasis | Organoids | Pancreas | Pancreatic Neoplasms

Data used in this publication

None found

Associated grants

  • Agency: NCI NIH HHS, Id: P30 CA093373
  • Agency: NCI NIH HHS, Id: R01 CA188134
  • Agency: NCI NIH HHS, Id: R01 CA190092
  • Agency: NCI NIH HHS, Id: R50 CA211506
  • Agency: NIDDK NIH HHS, Id: P30 DK089502
  • Agency: NCI NIH HHS, Id: P50 CA101955
  • Agency: NCI NIH HHS, Id: P50 CA127297
  • Agency: NCI NIH HHS, Id: R50 CA211462
  • Agency: NCI NIH HHS, Id: T32 CA126607
  • Agency: NCI NIH HHS, Id: U10 CA180944
  • Agency: NCI NIH HHS, Id: P30 CA045508
  • Agency: NCI NIH HHS, Id: U01 CA168409
  • Agency: NCI NIH HHS, Id: F32 CA180717
  • Agency: NCI NIH HHS, Id: P01 CA013106
  • Agency: NIH HHS, Id: S10 OD020122

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