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 behaviour. Understanding changes that occur to the ECM during cancer progression, and halting or reversing these changes, may alter cancer cell signalling, facilitate better penetration of therapeutics into the tumour and improve patient outcomes.
We have studied the extracellular matrix surrounding tumours from the PyMT mouse 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. High expression of PXDN was associated with worse patient outcomes in the clinic. We have confirmed that targeting of PXDN in pre-clinical in vivo mouse models of breast cancer resulted in slower tumour growth and improved survival. Investigations are now underway to determine the effects of PXDN targeting on the collagen IV content and microenvironment composition of tumours in breast cancer, and determining whether alterations in PXDN levels in cancer and/or stromal cells changes their ability to invade and metastasize.