Protein Kinase D2 controls pancreatic cancer cell invasion by secretion of trypsins PRSS1 and 3 as well as matrix-metalloproteases

The elucidation of signaling pathways regulating pancreatic cancer cell invasive properties is pivotal to control and develop strategies against metastasis. Protein Kinase D2 (PKD2) is strongly expressed in pancreatic cancer cells. We have recently identified PKD2 as a key regulator of trypsin (PRSS1, PRSS3) as well as matrix-metalloprotease (MMP) secretion in pancreatic cancer cells. PKD2 enhances PRSS1 and 3 expression as well as secretion. Both proteases are involved in cleavage of surface proteins such as the cell-cell adhesion protein E-Cadherin. Cleavage of E-Cadherin by trypsins generates fragments which interfere with cell-cell adhesion. PKD2 thus enhances pancreatic cancer cell scattering and invasion in 3D ECM culture. Inhibitors against PRSS1 and blocking antibodies against cancerogenic, inhibitor-resistant Mesotrypsin (PRSS3) reconstitute cell-cell adhesion. Inhibition of PRSS3 also blocks invasion and scattering in 3D ECM assays. In addition to regulation of trypsins we have identified PKD2 as a vital regulator of MMP expression as well as secretion adding to the above described invasive phenotype. Knockdown of regulated MMPs in PKD2 expressing pancreatic cancer cells thus further inhibits invasion in 3D culture. PKD2 therefore is a key novel pro-invasive kinase controlling cell invasion and scattering into the ECM matrix. We are currently investigating whether these properties will also affect invasion in vivo and metastasis fostering pancreatic tumor progression.