Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and metastatic tumour with poor prognosis. With a current survival rate of around 7%, it represents a significant burden of disease and complex therapeutic challenge.
PDAC is characterised by extensive extracellular matrix (ECM) remodelling leading to significant changes in both the biochemical and biomechanical properties of the tissue. In particular, PDAC typically presents with excessive deposition of fibrillar collagens within and surrounding tumours. These changes, driven by both tumour and stromal cells, feed back to drastically alter cell behaviour to drive pathological progression of the disease.
Lysyl oxidases, secreted by both cancer cells and CAFs are a family of secreted copper-dependent enzymes that post-translationally remodel the ECM through cross-linking collagens. They are critical in the biogenesis of fibrillar collagens and the incorporation of mature collagen fibrils into the ECM. To date, a functional role for lysyl oxidases has been reported in almost all solid tumours. High LOX family expression signatures are associated with PDAC and represent a critical mediator of the desmoplastic response in these tumours.
Using a novel LOX family inhibitor, we have found that blocking LOX activity reduces collagen crosslinking, collagen deposition and organisation of the ECM architecture. This leads to alterations in cancer cell ability to invade the surrounding ECM, as well as modulating sensitivity to standard of care therapies.
Our data suggest that the inhibition of LOX family members may represent a viable therapeutic option to improve outcome in PDAC.