ECTS Abstracts (2015) 1 S2.2

Lysyl-oxidase and the pre-metastatic bone niche

Alison Gartland, Thomas R Cox, Robin M H Rumney, Erwin M Schoof, Lara Perryman, Anette M Høye, Ankita Agrawal, Demelza Bird, Norain Ab Latif, Hamish Forrest, Holly R Evans, Iain D Huggins, Georgina Lang, Rune Linding & Janine T Erler

Sheffield, UK.

Lysyl oxidase (LOX) is an exciting new potential therapeutic target for the treatment and prevention of metastatic disease. We and others have shown that LOX is highly expressed by invasive/metastatic cancer cells, enhances tumour progression and that patients with high LOX expression had lower metastasis-free survival. We have also shown that LOX is critical for pre-metastatic niche formation in soft-tissue (lungs, liver and brain) enhancing bone marrow-derived cell invasion and thereby enabling colonisation of metastasising tumour cells. More recently we have begun to unravel the role of LOX in the bone pre-metastatic niche, in particular the early events governing osteolytic lesion formation. Using multiple in vitro and in vivo models, and a large clinical cohort, we show that LOX gene expression is significantly correlated with osteotropism and bone relapse. We show that high expression of LOX in primary breast tumours or systemic delivery of LOX in vivo leads to osteolytic lesion formation, and that silencing or inhibition of LOX activity abrogates this. The enzymatic activity of tumour-secreted LOX affects both osteoclasts and osteoblasts, disrupting normal bone homeostasis leading to bone lesion formation. These changes and lesions occur prior to tumour cell arrival in the bone and act to provide the initial foothold for circulating tumour cells to colonise the niche and form bone metastases. Mechanistically, we identify tumour-secreted LOX as a novel regulator of osteoclastogenesis through NFATc1 transcription factor translocation. In summary, we have uncovered a novel step in bone metastasis and mechanism of bone homeostatic regulation, opening up new opportunities for therapeutic intervention with important clinical implications.