Inhibition of QSOX1, a Modulator of Stromal Extracellular Matrix, Curbs Cancer Growth and Metastasis in Murine Cancer Models

The extracellular matrix (ECM) is known to play an important role in tumor progression and dissemination, but few points of intervention targeting ECM of the tumor microenvironment have been exploited therapeutically to date. Recent observations suggest that the enzymatic introduction of disulfide bond cross-links into the ECM is a process that may be modulated in the context of cancer. Specifically, Quiescin sulfhydryl oxidase 1 (QSOX1) is a catalyst of disulfide bond formation secreted from ECM-producing fibroblasts and over-expressed in many adenocarcinomas and their associated stroma. Our lab identified a role for QSOX1 in the assembly of the ECM, in particular for incorporation of certain isotypes of the protein laminin. Without laminin incorporation, the ECM cannot support adhesion and migration of tumor-derived epithelial cells. Motivated by the hypothesis that QSOX1 is involved in modulating ECM to make it more supportive of tumor growth and metastasis, our laboratory has developed monoclonal antibody inhibitors of QSOX1. Treating fibroblasts with these inhibitors while they were producing ECM led to inhibition of adhesion and migration of cancer cells through the fibroblast layer. Therefore, we suggest that controlling the activity of QSOX1 could be an anti-metastatic cancer therapy. Experiments have been conducted using the antibody in in vivo mouse breast cancer and melanoma models and in human triple-negative breast cancer xenografts. In these preclinical studies, we found that inhibition of QSOX1 decreases tumor progression and metastases. Therefore, we suggest that QSOX1 inhibitory antibody can be used as an ECM-directed therapy to complement other approaches to the treatment of metastatic adenocarcinomas.