title: Targeting ROR1 inhibits epithelial-mesenchymal transition and metastasis.
abstract: Metastasis is responsible for 90% of cancer-related deaths. Strategies are needed that can inhibit the capacity of cancer cells to migrate across the anatomic barriers and colonize distant organs. Here, we show an association between metastasis and expression of a type I receptor tyrosine kinase-like orphan receptor, ROR1, which is expressed during embryogenesis and by various cancers, but not by normal postpartum tissues. We found that expression of ROR1 associates with the epithelial-mesenchymal transition (EMT), which occurs during embryogenesis and cancer metastasis. Breast adenocarcinomas expressing high levels of ROR1 were more likely to have gene expression signatures associated with EMT and had higher rates of relapse and metastasis than breast adenocarcinomas expressing low levels of ROR1. Suppressing expression of ROR1 in metastasis-prone breast cancer cell lines, MDA-MB-231, HS-578T, or BT549, attenuated expression of proteins associated with EMT (e.g., vimentin, SNAIL-1/2, and ZEB1), enhanced expression of E-cadherin, epithelial cytokeratins (e.g., CK-19), and tight junction proteins (e.g., ZO-1), and impaired their migration/invasion capacity in vitro and the metastatic potential of MDA-MB-231 cells in immunodeficient mice. Conversely, transfection of MCF-7 cells to express ROR1 reduced expression of E-cadherin and CK-19, but enhanced the expression of SNAIL-1/2 and vimentin. Treatment of MDA-MB-231 with a monoclonal antibody specific for ROR1 induced downmodulation of vimentin and inhibited cancer cell migration and invasion in vitro and tumor metastasis in vivo. Collectively, this study indicates that ROR1 may regulate EMT and metastasis and that antibodies targeting ROR1 can inhibit cancer progression and metastasis.
authors.affiliation: UC San Diego Moores Cancer Center, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Cui
authors.forename: Suping
authors.initials: S
authors.lastname: Zhang
authors.forename: Liguang
authors.initials: L
authors.lastname: Chen
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Yu
authors.forename: George F
authors.initials: GF
authors.lastname: Widhopf
authors.forename: Jessie-F
authors.initials: JF
authors.lastname: Fecteau
authors.forename: Laura Z
authors.initials: LZ
authors.lastname: Rassenti
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D011379:Prognosis; D034622:RNA Interference; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors