Tumour metastasis is a complex process involving reciprocal interplay
between cancer cells and host stroma at both primary and secondary
sites, and is strongly influenced by microenvironmental
factors such as hypoxia. Tumour-secreted proteins play a crucial role
in these interactions and present strategic therapeutic potential.
Metastasis of breast cancer to the bone affects approximately 85%
of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed,
lead to debilitating skeletal complications and increased patient morbidity
and mortality. The molecular interactions governing the
early events of osteolytic lesion formation are currently unclear.
Here we show hypoxia to be specifically associated with bone relapse
in patients with oestrogen-receptor negative breast cancer. Global
quantitative analysis of the hypoxic secretome identified lysyl oxidase
(LOX) as significantly associated with bone-tropism and relapse.
High expression of LOX in primary breast tumours or systemic delivery
of LOX leads to osteolytic lesion formation whereas silencing or
inhibition of LOX activity abrogates tumour-driven osteolytic lesion
formation. We identify LOX as a novel regulator of NFATc1-driven
osteoclastogenesis,independent of RANK ligand, which disrupts normal
bone homeostasisleading to the formation of focal pre-metastatic
lesions. We show that these lesions subsequently provide a platform
for circulating tumour cells to colonize and form bone metastases.
Our study identifies a novel mechanism of regulation of bone homeostasis
and metastasis, opening up opportunities for novel therapeutic
intervention with important clinical implications.
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)