title: Tumor-secreted LOXL2 activates fibroblasts through FAK signaling.
abstract: Cancer-associated fibroblasts enhance cancer progression when activated by tumor cells through mechanisms not yet fully understood. Blocking mammary tumor cell-derived lysyl oxidase-like 2 (LOXL2) significantly inhibited mammary tumor cell invasion and metastasis in transgenic and orthotopic mouse models. Here, we discovered that tumor-derived LOXL2 directly activated stromal fibroblasts in the tumor microenvironment. Genetic manipulation or antibody inhibition of LOXL2 in orthotopically grown mammary tumors reduced the expression of α-smooth muscle actin (α-SMA). Using a marker for reticular fibroblasts, it was determined that expression of α-SMA was localized to fibroblasts recruited from the host tissue. This marker also revealed that the matrix present in tumors with reduced levels of LOXL2 was more scattered compared with control tumors which exhibited matrices with dense, parallel alignments. Importantly, in vitro assays revealed that tumor-derived LOXL2 and a recombinant LOXL2 protein induced fibroblast branching on collagen matrices, as well as increased fibroblast-mediated collagen contraction and invasion of fibroblasts through extracellular matrix. Moreover, LOXL2 induced the expression of α-SMA in fibroblasts grown on collagen matrices. Mechanistically, it was determined that LOXL2 activated fibroblasts through integrin-mediated focal adhesion kinase activation. These results indicate that inhibition of LOXL2 in tumors not only reduces tumor cell invasion but also attenuates the activation of host cells in the tumor microenvironment.
  
  
  CONCLUSIONS
  These findings reveal new insight into the mechanisms of fibroblast activation, a novel function of LOXL2, and further highlight the importance of generating LOXL2-targeted therapies for the prevention of tumor progression and metastasis.
authors.affiliation: University of Copenhagen, Ole Maaløes Vej 5, Copenhagen 2200, Denmark. janine.erler@bric.ku.dk.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Barker
authors.forename: Demelza
authors.initials: D
authors.lastname: Bird
authors.forename: Georgina
authors.initials: G
authors.lastname: Lang
authors.forename: Janine T
authors.initials: JT
authors.lastname: Erler
mesh_terms: D016475:3T3 Cells; D000199:Actins / Q000235:genetics / Q000378:metabolism; D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D015398:Signal Transduction / Q000235:genetics*; D059016:Tumor Microenvironment
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D003094:Collagen; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; C485601:Loxl2 protein, mouse; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse