Aberrant expression of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) in pancreatic cancer leads to dichotomic functions

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers characterized by highly invasive growth into the surrounding peripancreatic fat tissue, where tumor cells can directly interact with adipocytes. Due to poor response to the currently available (radio)chemotherapies, there is an urgent need for advanced therapy concepts. The present study shows that ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13), a key factor in blood coagulation, is significantly overexpressed in human PDAC. Immunohistochemical analysis revealed that ADAMTS13 expression is associated with prolonged survival and negatively correlated with vascular density. In vitro and in vivo experiments demonstrate its partial induction by leptin. Mechanistically, CRISPR/Cas-mediated ADAMTS13 knockout in PDAC cells resulted in reduced migration and invasion. In an avian xenograft tumor model, ADAMTS13 loss led to increased vascularization, decreased vascular length, and diminished tumor growth, accompanied by reduced expression of multiple key angiogenic and angioplastic factors. Furthermore, loss of ADAMTS13 was associated with decreased expression of mesenchymal markers. In conclusion, we identified an aberrant expression and alternative function of ADAMTS13 in PDAC linked to tumor progression, plasticity, and angiogenesis, partly induced by the peripancreatic fat tissue, making this metalloproteinase an interesting target for personalized therapies.