Background: The ductal adenocarcinomas of the pancreas belongs to the most aggressive malignancies with an overall 5-year survival rate of less than 5%. Characteristics of this particular tumor entity are the early local invasion and the development of distant metastases. Genetic and epigenetic alterations during development and progression of pancreatic ductal adenocarcinomas (PDAC) are well known. Orthotopic models were used to correlate genetic and epigenetic data with tumor biology to find specific alterations responsible for metastasis formation.Methods: 16 human PDAC cell lines of varying invasive and metastatic potential and different origin were used in murine orthotopic PDAC models. Using standardized dissemination scores, local infiltration and metastatic spread were assessed. RNA and microRNA expression was studied in Microarrays and Taqman Low Density Array. Quantitative RT-PCR and western blots were used for expression validation.Results: According to metastatic potential cell lines were classified into 3 hierarchical groups. In highly-metastatic PDAC, a significant induction of EP300 encoding miR-194 (fold change: 49.34), miR-200b (fold change: 28.36), miR-200c (fold change: 17.39), miR-429 (fold change: 15.23) (p<0.05) and corresponding, a decreased expression of EP300 mRNA (p<0.0001) and protein (p<0.05) for highly-metastatic PDAC with liver metastases were detected compared to non- or marginal metastatic cell lines. These alterations did not correlate with local tumor growth.Conclusion: In PDAC, epigentic alterations with upregulated EP300 encoding miR-194, miR-200b, miR-200c and miR-429 are related to downregulated EP300 mRNA and protein. These results demonstrate that microRNAs are able to modulate the expression of metastasis specific suppressor genes. In addition, these data suggest diagnostic and therapeutic opportunities for EP300 and its encoding miRNAs in PDAC.