Homeostasis of the extracellular matrix (ECM) is critical for correct organ and tissue function. Both the biochemical and biomechanical properties of the ECM contribute to modulating the behaviour of resident cells and are more than just passive bystanders. In tissue diseases such as cancer, the ECM undergoes significant change. These changes, driven by both tumour and stromal cells, feed into the pathological progression of the disease.
Lysyl oxidases are a family of secreted copper-dependent enzymes that post-translationally remodel the ECM through cross-linking collagens and elastin. To date, a functional role for lysyl oxidases has been reported in almost all solid tumours. Our work has shown that LOX-driven ECM remodelling is critical in modulating Src, FAK and Akt signalling activation, VEGF-driven angiogenesis, and nFATc1-mediated osteoclastogenesis [1]. Thus, lysyl oxidases play important and crucial roles in primary tumour growth and invasion; the generation of pre-metastatic niches; the progression of organ fibrosis and tumour desmoplasia; and can be used to stratify patients that will respond favourably to treatment with already approved clinical drugs, including bisphosphonates, and Src, Akt, VEGF and FAK inhibitors.
Furthermore, we have developed new approaches to visualise and study ECM remodelling in cancer. We have established a novel in situ decellularisation approach (ISDoT), which allows high-resolution fluorescence and second harmonic imaging, as well as quantitative proteomic interrogation of the 3D structure and spatial organisation of the ECM [2]. Understanding at the molecular level how the changing ECM landscape facilitates tumour progression is an important step in the treatment of cancer