title: Tumor-associated Endo180 requires stromal-derived LOX to promote metastatic prostate cancer cell migration on human ECM surfaces.
abstract: The diverse composition and structure of extracellular matrix (ECM) interfaces encountered by tumor cells at secondary tissue sites can influence metastatic progression. Extensive in vitro and in vivo data has confirmed that metastasizing tumor cells can adopt different migratory modes in response to their microenvironment. Here we present a model that uses human stromal cell-derived matrices to demonstrate that plasticity in tumor cell movement is controlled by the tumor-associated collagen receptor Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) and the crosslinking of collagen fibers by stromal-derived lysyl oxidase (LOX). Human osteoblast-derived and fibroblast-derived ECM supported a rounded 'amoeboid-like' mode of cell migration and enhanced Endo180 expression in three prostate cancer cell lines (PC3, VCaP, DU145). Genetic silencing of Endo180 reverted PC3 cells from their rounded mode of migration towards a bipolar 'mesenchymal-like' mode of migration and blocked their translocation on human fibroblast-derived and osteoblast-derived matrices. The concomitant decrease in PC3 cell migration and increase in Endo180 expression induced by stromal LOX inhibition indicates that the Endo180-dependent rounded mode of prostate cancer cell migration requires ECM crosslinking. In conclusion, this study introduces a realistic in vitro model for the study of metastatic prostate cancer cell plasticity and pinpoints the cooperation between tumor-associated Endo180 and the stiff microenvironment imposed by stromal-derived LOX as a potential target for limiting metastatic progression in prostate cancer.
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK.|Centre for Cutaneous Research, Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, E1 2AT, UK.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Caley
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK.|Division of Cancer Studies, King's College London, New Hunts House, Guys Campus, London, SE1 1UL, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: King
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK.|Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.|Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Neel
authors.initials: N
authors.lastname: Shah
authors.affiliation: School of Biological, Biomedical & Environmental Sciences, University of Hull, Cottingham Road, Hull, HU6 7RX, UK.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK.|Departamento de Genética, Facultad de Medicina, Universidad de la República (UDELAR), Montevideo, Uruguay.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rodriguez-Teja
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK.
authors.forename: Julian H
authors.initials: JH
authors.lastname: Gronau
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Waxman
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK. j.sturge@hull.ac.uk.|School of Biological, Biomedical & Environmental Sciences, University of Hull, Cottingham Road, Hull, HU6 7RX, UK. j.sturge@hull.ac.uk.
authors.forename: Justin
authors.initials: J
authors.lastname: Sturge
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010006:Osteoblasts / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: C404106:MRC2 protein, human; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D008249:Protein-Lysine 6-Oxidase
keywords: Bone; Cell migration; Collagen; Fibroblast; Osteoblast; Prostate cancer