title: In melanoma, beta-catenin is a suppressor of invasion.
abstract: Cell-type-specific signalling determines cell fate under physiological conditions, but it is increasingly apparent that also in cancer development the impact of any given oncogenic pathway on the individual cancer pathology is dependent on cell-lineage-specific molecular traits. For instance in colon and liver cancer canonical Wnt signalling produces increased cytoplasmic and nuclear localised beta-catenin, which correlates with invasion and poor prognosis. In contrast, in melanoma increased cytoplasmic and nuclear beta-catenin is currently emerging as a marker for good prognosis, and thus seems to have a different function compared with other cancer types; however, this function is unknown. We discovered that in contrast to its function in other cancers, in melanoma, beta-catenin blocks invasion. We demonstrate that this opposing role of nuclear beta-catenin in melanoma is mediated through MITF, a melanoma-specific protein that defines the lineage background of this cancer type. Downstream of beta-catenin MITF not only suppresses the Rho-GTPase-regulated cell morphology of invading melanoma cells, but also interferes with beta-catenin-induced expression of the essential collagenase MT1-MMP, thus affecting all aspects of an invasive phenotype. Importantly, overexpression of MITF in invasive colon cancer cells modifies beta-catenin-directed signalling and induces a 'melanoma phenotype'. In summary, the cell-type-specific presence of MITF in melanoma affects beta-catenin's pro-invasive properties otherwise active in colon or liver cancer. Thus our study reveals the general importance of considering cell-type-specific signalling for the accurate interpretation of tumour markers and ultimately for the design of rational therapies.
authors.affiliation: Molecular Cancer Studies, Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: I
authors.initials: I
authors.lastname: Arozarena
authors.forename: H
authors.initials: H
authors.lastname: Bischof
authors.forename: D
authors.initials: D
authors.lastname: Gilby
authors.forename: B
authors.initials: B
authors.lastname: Belloni
authors.forename: R
authors.initials: R
authors.lastname: Dummer
authors.forename: C
authors.initials: C
authors.lastname: Wellbrock
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000556:secondary; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D051176:beta Catenin; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D020741:rho GTP-Binding Proteins