Identification of mechanisms leading to preneoplastic lesions in the pancreas

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. High mortality rate is a consequence of late diagnosis which results from the lack of symptoms at early stages of the disease. Therefore, understanding mechanisms initiating PDAC is of outmost importance. PDAC can originate from acinar cells that undergo acinar-to-ductal metaplasia. This lesion can evolve to pancreatic intraepithelial neoplasia and further to invasive cancer. In this context, we have identified a gene regulatory network, involving microRNAs (let-7b, miR-495), transcription factors (SOX9, HNF6) and EGF signaling, and whose perturbation promotes metaplasia. We also demonstrated that lesions in pancreatic ductal cells can give rise to acinar-to-ductal metaplasia. In conclusion, our work identified molecular, cellular and tissular mechanisms that favor development of precancerous lesions of PDAC.