CYLD-a potential mediator of site-specific melanoma metastasis

FOR 2127: Selektion und Adaptation während der metastatischen Krebsprogression

In recent studies we identified a SNAIL-dependent signalling pathway that induces downregulation of CYLD which is an important tumour suppressor, relevant in melanoma metastasis. We further could show that loss of CYLD expression leads to induction of proliferation and metastasis by activation of NFkB and regulation of CyclinD1 and N-cadherin expression. Importantly, in melanoma patients we could link the loss of CYLD expression to Clark level, tumour thickness, and progression free and overall survival.In further experiments, we generated a Cyld-deficient mouse on the background of a melanoma-prone mouse model (Grm1-transgene), a model for spontaneously developing melanoma with 100% penetrance. These Grm1/Cyld knockout mice have a significantly earlier tumour onset and multiple local skin metastases compared to the mice control group which developed no strong local dermal invasion.In the project we intend to further exploit this mouse model and we aim to determine in detail the role of CYLD in steps of metastasis. Regarding this we are interested to discover the invasive routes which are taken by the disseminated tumour cells and we want to understand the molecular timeline of metastases. Furthermore, comparing nevi with melanoma and melanoma metastasis, respectively on differences in gene-, protein-, and miRNA expression, genomic-, epigenetic-, and signalling changes we want to define new molecular gatekeepers and their particular role in these processes.