In melanoma, beta-catenin is a suppressor of invasion

• Published in: Oncogene Vol. 30; no. 45; pp. 4531 - 4543
• Main Authors: Arozarena, I, Bischof, H, Gilby, D, Belloni, B, Dummer, R, Wellbrock, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.11.2011; Nature Publishing Group
• Subjects: 631/208/199; 631/80/84/2336; 692/699/67/1813/1634; Apoptosis; beta Catenin - metabolism; Biological and medical sciences; Biomarkers, Tumor - blood; catenin; Cell adhesion & migration; Cell Biology; Cell fate; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Collagen; Collagenase; Colon; Colon cancer; Colonic Neoplasms - metabolism; Colonic Neoplasms - secondary; Cytology; Dermatology; Development and progression; Fundamental and applied biological sciences. Psychology; Gene expression; Guanine nucleotide-binding protein; Human Genetics; Humans; Internal Medicine; Invasiveness; Liver cancer; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Matrix Metalloproteinase 14 - metabolism; Medical sciences; Medicine; Medicine & Public Health; Melanoma; Melanoma - metabolism; Melanoma - pathology; Metastasis; Microphthalmia-associated transcription factor; Microphthalmia-Associated Transcription Factor - metabolism; Molecular and cellular biology; Neoplasm Invasiveness; Oncology; original-article; Phenotypes; Prognosis; Proteins; rho GTP-Binding Proteins - metabolism; Risk factors; Signal transduction; Skin cancer; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Wnt protein; β-Catenin; United Kingdom; Rho; MMP; melanoma; MITF; ROCK; invasion; Enzyme; Triphosphoric monoester hydrolases; dGTPase; Esterases; Malignant tumor; Metastasis; Carcinogenesis; Malignant melanoma; Hydrolases; Catenin; Cancer
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/onc.2011.162

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.