"Enhancer Reprogramming Promotes Pancreatic Cancer Progression and Metastasis"
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Using pancreatic organoid models, we found that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 and the transcriptional repressor EN1 responsible for the genes associated with enhancer activation and inactivation, respectively. Expression of FOXA1 and EN1 renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. Collectively, our study implicates enhancer reprogramming, FOXA1 and EN1 up-regulation, and a developmental transcription program in PDA metastasis.
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