Protein Kinase D2 (PKD2) controls pancreatic cancer cell invasion and angiogenesis by secretion of trypsins PRSS1 and 3 as well as matrix-metalloproteases

The elucidation of signaling pathways controlling pancreatic cancer cell invasion and angiogenesis is pivotal to control and develop strategies against metastasis. Protein Kinase D2 (PKD2) is strongly expressed in pancreatic cancer cells. It is a key regulator of trypsin (PRSS1, PRSS3) as well as matrix-metalloprotease 7 and 9 (MMP 7 and 9) expression and secretion. PRSS1 and 3 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. Trypsins also act upstream of MMPs, e.g. by processing pro-MMP9 to its active state. By controlling the secretion and activation of these proteases PKD2 enhances pancreatic cancer cell scattering and invasion in 3D ECM culture. Blocking antibodies against cancerogenic, inhibitor-resistant Mesotrypsin (PRSS3) reconstitute cell-cell adhesion. Inhibition of PRSS3 as well as MMP7 and 9 also blocks invasion and scattering in 3D ECM assays. In addition to regulation of invasive properties, MMP9 also enhances angiogenesis by releasing matrix-bound VEGF-A controlling its bio-availability and tumor vascularisation. PKD2 therefore is a key novel pro-invasive kinase which directly modulates tumor cell scattering, invasion and angiogenesis via secretion of distinct proteases in pancreatic cancer cells. We are currently investigating whether these properties will also affect invasion and angiogenesis in different in-vivo models thereby fostering pancreatic tumor progression.