title: The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase.
abstract: 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 homeostasis leading 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.
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), Copenhagen, DK-2200, Denmark.|Hypoxia and Metastasis Team, Cancer Research UK Tumour Cell Signalling Unit, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cox
authors.affiliation: The Mellanby Centre for Bone Research, The University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Robin M H
authors.initials: RMH
authors.lastname: Rumney
authors.affiliation: Cellular Signal Integration Group (C-SIG), Technical University of Denmark (DTU), Lyngby, DK-2800, Denmark.
authors.forename: Erwin M
authors.initials: EM
authors.lastname: Schoof
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), Copenhagen, DK-2200, Denmark.
authors.forename: Lara
authors.initials: L
authors.lastname: Perryman
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), Copenhagen, DK-2200, Denmark.
authors.forename: Anette M
authors.initials: AM
authors.lastname: Høye
authors.affiliation: The Mellanby Centre for Bone Research, The University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Ankita
authors.initials: A
authors.lastname: Agrawal
authors.affiliation: Hypoxia and Metastasis Team, Cancer Research UK Tumour Cell Signalling Unit, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Demelza
authors.initials: D
authors.lastname: Bird
authors.affiliation: The Mellanby Centre for Bone Research, The University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Norain Ab
authors.initials: NA
authors.lastname: Latif
authors.affiliation: The Mellanby Centre for Bone Research, The University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Hamish
authors.initials: H
authors.lastname: Forrest
authors.affiliation: The Mellanby Centre for Bone Research, The University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Holly R
authors.initials: HR
authors.lastname: Evans
authors.affiliation: The Mellanby Centre for Bone Research, The University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Iain D
authors.initials: ID
authors.lastname: Huggins
authors.affiliation: Hypoxia and Metastasis Team, Cancer Research UK Tumour Cell Signalling Unit, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Georgina
authors.initials: G
authors.lastname: Lang
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), Copenhagen, DK-2200, Denmark.|Cellular Signal Integration Group (C-SIG), Technical University of Denmark (DTU), Lyngby, DK-2800, Denmark.
authors.forename: Rune
authors.initials: R
authors.lastname: Linding
authors.affiliation: The Mellanby Centre for Bone Research, The University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Gartland
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), Copenhagen, DK-2200, Denmark.|Hypoxia and Metastasis Team, Cancer Research UK Tumour Cell Signalling Unit, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Janine T
authors.initials: JT
authors.lastname: Erler
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control / Q000556:secondary*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000473:pathology; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics
chemical_list: D050778:NFATC Transcription Factors; D011960:Receptors, Estrogen; D008249:Protein-Lysine 6-Oxidase