title: Lipid Osteoclastokines Regulate Breast Cancer Bone Metastasis.
abstract: Bone metastasis is a deadly consequence of cancers, in which osteoclast forms a vicious cycle with tumor cells. Bone metastasis attenuation by clinical usage of osteoclast inhibitors and in our osteopetrotic mouse genetic models with β-catenin constitutive activation or peroxisome proliferator-activated receptor γ deficiency fully support the important role of osteoclast in driving the bone metastatic niche. However, the mechanisms for this "partnership in crime" are underexplored. Here we show that osteoclasts reprogram their lipid secretion to support cancer cells. Metabolomic profiling reveals elevated prometastatic arachidonic acid (AA) but reduced antimetastatic lysophosphatidylcholines (LPCs). This shift in lipid osteoclastokines synergistically stimulates tumor cell proliferation, migration, survival, and expression of prometastatic genes. Pharmacologically, combined treatment with LPCs and BW-755C, an inhibitor of AA signaling via blocking lipoxygenase and cyclooxygenase, impedes breast cancer bone metastasis. Our findings elucidate key paracrine mechanisms for the osteoclast-cancer vicious cycle and uncover important therapeutic targets for bone metastasis.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: Jing Y
authors.initials: JY
authors.lastname: Krzeszinski
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Schwaid
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: Wing Yin
authors.initials: WY
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: Zixue
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, USA.|Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Gallegos
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts.|Clayton Foundation Laboratories of Peptide Biology and Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies, La Jolla, California.
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, USA.|Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D050356:Lipid Metabolism; D008244:Lysophosphatidylcholines; D055432:Metabolomics; D018345:Mice, Knockout; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000502:physiology*; D010012:Osteogenesis; D019899:Paracrine Communication
chemical_list: D016207:Cytokines; D008244:Lysophosphatidylcholines; D016718:Arachidonic Acid