Quiescin sulfhydryl oxidase 1 (QSOX1) is a catalyst of disulfide bond formation that undergoes regulated secretion from fibroblasts and is over-produced in many cancers, for example in prostate and pancreatic adenocarcinomas. We have recently shown that QSOX1 is required for incorporation of particular laminin isoforms into the basement membrane extracellular matrix and, as a consequence, for tumor cell penetration of this matrix. Moreover, we found increased secretion of QSOX1 from cancer-associated fibroblasts and an over-representation of QSOX1-positive fibroblasts in histological sections of patient tumors. The known role of laminins in integrin-mediated cell survival and motility suggests that controlling QSOX1 activity may provide a novel means of combating metastatic disease. With this motivation, we have developed a monoclonal antibody that binds and inhibits human QSOX1. Characterization of this antibody reveals that it blocks the first step in the QSOX1 dithiol/disulfide relay mechanism. The antibody thereby allows tight control of basement membrane composition, and in turn the migratory behavior of tumor cells, in co-culture models for tumor cell metastasis. Preliminary experiments have been conducted using the antibody to control mestastases in a tumor/fibroblast xenograft experiment in mice, and we are currently extending the antibody testing to a more comprehensive tumorgraft model. The QSOX1 inhibitory antibody will be a valuable tool for the study of the role of basement membrane components in cell migration and for cancer therapies based on manipulation of the tumor microenvironment.
