CYLD-a potential mediator of site-specific melanoma metastasis

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Unlike in cylindromatosis, downregulation of the de-ubiquitinase CYLD in melanoma, a highly aggressive tumour, is not caused by mutations in the CYLD gene but rather by a constitutive and high expression of the transcription factor SNAIL 1. The reduced CYLD level leads to BCL-3/p50/p52-dependent NFκB activation, which in turn triggers expression of genes such as cyclinD1 and N-cadherin. Elevated levels of cyclinD1 and N-cadherin promote melanoma proliferation and invasion. 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. Grm1/Cyld+/+ mice show no dermal or local invasion whereas Grm1/Cyld-/- mice present multiple local skin metastases and invasion into the muscle. In the project we intend to further exploit this mouse model and we aim to determine the impact of CYLD in efficient local metastasis and would like to transfer our new knowledge also to the event of distal site-specific metastasis, especially in liver, brain and lymph nodes. Regarding this we are interested to discover the invasive routes (e.g. lymphatic pathways), which are taken by the tumour cells and want to differentiate between molecular changes, which have an impact on the tumour cells themselves, and CYLD-dependent factors, which change the micro-environment (e.g. mast cells). We have performed RNA-Seq analysis of the tissue samples of nevi and primary tumours of both mice model subtypes. We will now characterize epigenetic regulation mechanisms, which are relevant for differences in metastatic behaviour. Furthermore, we will analyse miRNA expression and changes in murine tissue samples of the mouse model and murine cell lines, which we generated in the first funding period.