Lysyl oxidase secreted by hypoxic tumour cells is critical for pre-metastatic niche formation


Year:

Session type:

Janine Erler1, Kevin Bennewith2, Amato Giaccia2

1Institute of Cancer Research, London, UK, 2Stanford University, California, USA

Abstract

Lysyl oxidase secreted by hypoxic tumour cells is critical for pre-metastatic niche formation

Tumour hypoxia is present in all solid tumours, and is clinically associated with metastasis and poor survival. We previously demonstrated a critical role for hypoxia-induced secreted lysyl oxidase (LOX) in breast cancer metastasis. Here, we investigated how LOX enables metastatic growth by characterising its role in bone marrow-derived cell (BMDC) recruitment and pre-metastatic niche formation.

We monitored metastasis in an orthotopic model of breast cancer to investigate the sequence of events required for metastatic growth. We investigated a role for LOX in pre-metastatic niche formation by supplying LOX to mice bearing tumours with genetically inhibited LOX that are normally unable to develop metastases. We used conditioned media to generate pre-metastatic niches in non-tumour bearing mice, and investigated a role for LOX through supply and inhibtion of LOX. We examined the effects of LOX matrix modifications on BMDC recruitment and invasion.

We demonstrate that LOX secreted by hypoxic breast tumour cells binds to regions of elevated fibronectin expression at pre-metastatic sites, and co-operates in recruiting BMDCs and creating a permissive niche for incoming metastatic tumour cells. Supply of exogenous LOX can support metastatic growth, whereas inhibition of LOX disrupts pre-metastatic niche formation and development of metastases. LOX-mediated matrix modifications promote BMDC invasion through increased matrix metalloproteinase activity, which enhances the recruitment and invasion of BMDCs and metastasizing tumour cells.

Our findings demonstrate a critical role for LOX in pre-metastatic niche formation and support targeting LOX for the treatment and prevention of metastatic disease.