The molecular and cellular mechanisms underlying the development and progression of malignant melanoma as well as the development of therapy resistance are despite recent advances not sufficiently clarified. Therefore, the overall objective of our research is the analysis of potential new target molecules for future therapy of malignant melanoma. In our work we focus on critical nodal points in signal transmission in melanoma: transcription factors and signaling pathways involved in mediating melanoma progression and therapy resistance towards BRAF or MAPK inhibition and chemotherapeutic agents. We have focused i.e. on the effectors of PI3K/AKT-signaling pathways in human melanoma cells and the mechanisms that lead to activation of this pathway. We use human melanoma cell lines in different growth phases, which we can analyze either in monolayer or in co-culture with other skin-derived cells using complex human model systems as organotypic skin reconstructs and spheroids in order to investigate the influence of the microenvironment on human melanoma cell growth. Furthermore, we established human BRAF- and/or MEK-inhibitor resistant melanoma cells to analyze the influence of blocking individual factors on acquired therapy resistance in vitro or in in vivo mouse models for metastasis.
In our own previous work we have obtained evidence that the transcription and translation factor YB-1, the kinase casein kinase 1alpha (CK1α), beta-catenin, Stat3 and p53 signaling play a critical role in the progression and therapy resistance of melanoma. We have found that CK1α has a key role in the determination of β-catenin stability and transcriptional activity in melanoma cells. YB-1 and β-catenin are upregulated in vivo during melanoma progression and influence melanoma cell viability and invasive growth. Interestingly, both factors act as a transcriptional activator in many cancer related signaling pathways. Recently, we demonstrated that β-catenin interacts with Stat3 after chronic MAPK inhibition and both together cooperate in the acquisition and maintenance of resistance towards BRAF inhibition independent of the canonical Wnt signaling pathway. YB-1, Stat3 and beta-catenin are thus promising targets in melanoma therapy, since they control the expression of a number of oncogenes.