In solid cancers, tumour cells are surrounded by a supportive extracellular matrix (ECM) of proteins and stromal cells that form the tumour microenvironment. This microenvironment acts both as a physical and biological barrier for therapy penetration into the tumour, reducing the efficiency of these therapies, as well as directly interacting with cancer cells to alter tumour behavior. The interaction between the cancer cells and ECM is reciprocal with cancer cells altering the ECM and contributing to its increased deposition or remodeling, which in turn changes the ECM mediated signals received by the cells. Understanding changes that occur to the ECM during cancer progression, and halting or reversing these changes, may alter cancer cell signaling, facilitate better penetration of therapeutics into the tumour and improve patient outcomes.
We have studied the extracellular matrix surrounding tumours from the KPC mouse model of pancreatic ductal adenocarcinoma and the PyMT model of breast cancer. We identified a collagen IV cross-linking enzyme, peroxidasin (PXDN), which is upregulated in cancer ECM compared to healthy stroma and plays an important role in the desmoplastic response of tumours. PXDN is secreted into the conditioned media of PyMT and KPC CAFs as well as KPC cancer cells derived from our mouse models. Genetic silencing or pharmacological inhibition of PXDN in KPC and PyMT cells in in vitro and in vivo models of disease are underway to investigate the role that PXDN plays in remodeling of the tumour microenvironment, cancer progression and response to standard-of-care chemotherapy in pancreatic and breast cancer.