Matrix metalloproteinase‐7 controls pancreatic acinar cell transdifferentiation by activating the notch signaling pathway

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States, demonstrating the lowest five‐year survival rate of any cancer. An important observation made in cases of PDAC is the consistent presence of putative preneoplastic lesions, known as metaplastic ducts, which arise from a process known as acinar‐to‐ductal metaplasia. Molecular dissection of this process in vitro has shown that primary acinar cells, in response to EGF receptor ligands, can transdifferentiate into duct‐like epithelia in a Notch pathway dependent manner. Here we show that in vitro acinar transdifferentiation is dependent on Matrix Metalloproteinase‐7 (MMP‐7), a proteinase expressed in most metaplastic epithelia in vivo. MMP‐7 was found to be required for Notch activation, leading to dedifferentiation of acinar cells to a nestin‐positive transitional cell. We also showed that ADAM‐10, but not ADAM‐17, may be necessary for MMP‐7's effect on Notch activity. MMP‐7 activity was also found to be sufficient to induce the process, indicating that molecular signals capable of initiating MMP‐7 expression also have the potential to induce formation of metaplastic epithelia in the pancreas.