title: A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis.
abstract: Wnt signaling plays a critical role in embryonic development, and genetic aberrations in this network have been broadly implicated in colorectal cancer. We find that the Wnt receptor Frizzled2 (Fzd2) and its ligands Wnt5a/b are elevated in metastatic liver, lung, colon, and breast cancer cell lines and in high-grade tumors and that their expression correlates with markers of epithelial-mesenchymal transition (EMT). Pharmacologic and genetic perturbations reveal that Fzd2 drives EMT and cell migration through a previously unrecognized, noncanonical pathway that includes Fyn and Stat3. A gene signature regulated by this pathway predicts metastasis and overall survival in patients. We have developed an antibody to Fzd2 that reduces cell migration and invasion and inhibits tumor growth and metastasis in xenografts. We propose that targeting this pathway could provide benefit for patients with tumors expressing high levels of Fzd2 and Wnt5a/b.
authors.affiliation: Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Warren Alpert 524, Boston, MA 02115, USA.
authors.forename: Taranjit S
authors.initials: TS
authors.lastname: Gujral
authors.affiliation: Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Warren Alpert 524, Boston, MA 02115, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Chan
authors.affiliation: Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Warren Alpert 524, Boston, MA 02115, USA.
authors.forename: Leonid
authors.initials: L
authors.lastname: Peshkin
authors.affiliation: Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Warren Alpert 524, Boston, MA 02115, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Sorger
authors.affiliation: Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Warren Alpert 524, Boston, MA 02115, USA. Electronic address: marc@hms.harvard.edu.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Kirschner
authors.affiliation: Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Warren Alpert 524, Boston, MA 02115, USA. Electronic address: gavin_macbeath@harvard.edu.
authors.forename: Gavin
authors.initials: G
authors.lastname: MacBeath
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D051157:Frizzled Receptors / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology; D009368:Neoplasm Transplantation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: C489742:FZD2 protein, human; D051157:Frizzled Receptors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051153:Wnt Proteins