PTEN and melanomagenesis.

The PI3K-PTEN-AKT signaling pathway is involved in various cellular activities, including proliferation, migration, cell growth, cell survival and differentiation during adult homeostasis as well as in tumorigenesis. It has been suggested that the constitutive activation of PI3K/AKT signaling with concurrent loss of function of the tumor suppressor molecule PTEN contributes to cancer formation. Members of the PI3K-PTEN-AKT pathway, including these proteins and mTOR, are altered in melanoma tumors and cell lines. A hallmark of activation of the pathway is the loss of function of PTEN. Indeed, loss of heterozygosity of PTEN has been observed in approximately 30% of human melanomas, implicating this signaling pathway in this cancer. PI3K signaling activation, via loss of PTEN function, can inhibit proapoptotic genes such as the FoxO family of transcription factors, while inducing cell growth- and cell survival-related elements such as p70S6K and AKT. Determining how the PI3K-PTEN-AKT signaling pathway, alone or in cooperation with other pathways, orchestrates the induction of target genes involved in a diverse range of activities is a major challenge in research into melanoma initiation and progression. Moreover, the acquisition of basic knowledge will help patient management with appropriate therapies that are already, or will shortly be, on the market.

A role for Dynlt3 in melanosome movement, distribution, acidity and transfer.

Skin pigmentation is dependent on cellular processes including melanosome biogenesis, transport, maturation and transfer to keratinocytes. However, how the cells finely control these processes in space and time to ensure proper pigmentation remains unclear. Here, we show that a component of the cytoplasmic dynein complex, Dynlt3, is required for efficient melanosome transport, acidity and transfer. In Mus musculus melanocytes with decreased levels of Dynlt3, pigmented melanosomes undergo a more directional motion, leading to their peripheral location in the cell. Stage IV melanosomes are more acidic, but still heavily pigmented, resulting in a less efficient melanosome transfer. Finally, the level of Dynlt3 is dependent on ß-catenin activity, revealing a function of the Wnt/ß-catenin signalling pathway during melanocyte and skin pigmentation, by coupling the transport, positioning and acidity of melanosomes required for their transfer.

A caveolin-dependent and PI3K/AKT-independent role of PTEN in ß-catenin transcriptional activity.

Loss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of ß-catenin independent of the PI3K-AKT-GSK3ß axis. The absence of PTEN leads to caveolin-1 (CAV1)-dependent ß-catenin transcriptional modulation in vitro, cooperates with NRAS(Q61K) to initiate melanomagenesis in vivo and induces efficient metastasis formation associated with E-cadherin internalization. The CAV1-ß-catenin axis is mediated by a feedback loop in which ß-catenin represses transcription of miR-199a-5p and miR-203, which suppress the levels of CAV1 mRNA in melanoma cells. These data reveal a mechanism by which loss of PTEN increases CAV1-mediated dissociation of ß-catenin from membranous E-cadherin, which may promote senescence bypass and metastasis.

Human relevance of NRAS/BRAF mouse melanoma models.

Melanoma is a major problem for many individuals worldwide. Although no effective treatment is available, promising new strategies are being developed. A better understanding of the inner workings of the disease would undoubtedly lead to improved treatments. Mouse melanoma models have been used to elucidate many key regulatory pathways involved in melanoma initiation and progression, and models with mutations in the oncogenes RAF and RAS have been particularly informative. Here, we summarize and evaluate the human relevance of various RAF and RAS mouse melanoma models and their contribution to our understanding of melanoma.