In melanoma, beta-catenin acts as suppressor of invasion through a cell-type specific mechanism

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 appears to have a different function compared to 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.