Mo1401 Serum Metabolomics As the Diagnostic Application for Early Diagnosis of Pancreatic Cancer

manipulating the activity of BMP signalling in vitro. Methods: We performed an immunohistochemical analysis of the expression of BMP signalling components (BMPReceptors and SMADs) in a tissue microarray of 41 patients with pancreatic ductal adenocarcinoma (PDAC) and correlated this to patients' survival. We also compared the expression levels of these components in 51 primary pancreatic tumours with 17 metastases. shRNA against SMAD4 and a plasmid encoding SMAD4 was used to investigate the effect of SMAD4 loss in vitro. The BMPReceptor expression was manipulated using siRNA against in a panel of pancreatic cancer cell lines and effects were analyzed using proliferation and invasion assays. Results: Loss of SMAD4 in patients with PDAC is associated with significantly worse survival (p= 0.025). Moreover, SMAD4 loss is more frequent in the metastases samples compared to the primary tumours (65% vs. 47%). Loss of SMAD4 induces transformation of cancer cells into more aggressive mesenchymal cell type with properties of the cancer stem cells, which proliferate slower and are more resistant to chemotherapy. Importantly, in a group of patients with intact positive SMAD4 expression loss of BMPR1a correlates significantly with a poor prognosis (p=0.02). Activation of BMP signalling in SMAD4 positive cancer cells leads to reduced proliferation, migration and invasion. The importance of BMP Receptor loss is confirmed by showing an increase in proliferation and invasion of pancreatic cancer cells after siRNA mediated knockdown of the BMPReceptors or opposite effect after restitution of BMPR. Conclusion: Loss of BMPR1a and SMAD4 results in poor survival in patients with pancreatic cancers. Inactivation of the BMP pathway increases aggressive tumourigenic properties of pancreatic cancer cells, while activation of the BMP pathway in pancreatic cancer reduces invasive metastatic phenotype of cells. Our data suggest that the BMP pathway can be an attractive target for future therapeutic interventions.