Down-regulation of FZD3 receptor suppresses growth and metastasis of human melanoma independently of canonical WNT signaling
Menée sur des cellules de mélanome d'origine humaine et à l'aide d'une xénogreffe sur un modèle murin, cette étude met en évidence un mécanisme par lequel la réduction de l'expression du récepteur FZD3, indépendamment de la voie de signalisation canonique des protéines WNT, supprime la croissance tumorale et le développement de métastases
In malignant melanoma, one of the most aggressive cancers, the components of the WNT pathway are frequently deregulated and have been shown to drive self-renewal and metastatic progression of melanoma cells. Identifying tumorigenic properties of key members of the WNT signaling network in the pathogenesis of melanoma represents a pivotal task in the field and underlies successful design of targeted therapeutic approaches. In the present study, we characterized Frizzled 3 receptor (FZD3) as a critical factor underlying tumorigenic properties of aggressive human melanoma. Using in vivo and in vitro tumorigenic assays, combined with functional transcriptomics analysis of FZD3 knockdown in human patient-derived cells, we determined key signaling nodes regulated by FZD3 activity during malignant transformation.Frizzled 3 receptor (FZD3) plays an important role in the homeostasis of the neural crest and its derivatives, which give rise to pigment-synthesizing cells, melanocytes. While the role for FZD3 in specification of the melanocytic lineage from neural crest is well established, its significance in the formation of melanoma, its associated malignancy, is less understood. In this study we identified FZD3 as a critical regulator of human melanoma tumorigenesis. Down-regulation of FZD3 abrogated growth, colony-forming potential, and invasive capacity of patient-derived melanoma cells. Xenotransplantation of tumor cells with down-regulated FZD3 levels originating from melanomas carrying the BRAF(V600) mutation uniformly suppressed their capacity for tumor and metastasis formation. FZD3 knockdown leads to the down-regulation of the core cell cycle protein components (cyclins D1, E2, B1, and CDKs 1, 2, and 4) in melanomas with a hyperactive BRAF oncogene, indicating a dominant role of this receptor during melanoma pathogenesis. Enriched pathway analysis revealed that FZD3 inhibits transcriptional networks controlled by CREB5, FOXD1, and ATF3, which suppress the activity of MAPK-mediated signaling. Thus, FZD3 establishes a positive-feedback mechanism that activates MAPK signal transduction network, critical to melanoma carcinogenesis. Importantly, high levels of FZD3 mRNA were found to be correlated with melanoma advancement to metastatic stages and limited patient survival. Changes in gene-expression patterns mediated by FZD3 activity occur in the absence of nuclear β-catenin function, thus representing an important therapeutic target for the melanoma patients whose disease progresses independent of canonical WNT signaling.