Identification of tumor-cell intrinsic and microenvironmental factors influencing lymph node colonization in melanoma.

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Most cancers spread early through lymphatic vessels to lymph nodes in the ipsilateral, regional lymph node basin. Melanoma spread to sentinel (SLNs) and non-sentinel nodes (NSLNs) of the regional nodal basin are major predictors for melanoma outcome and these tissues offer the unique opportunity to study tumor cell-intrinsic and microenvironmental factors governing selection and adaptation of disseminated cancer cells. Our previous work revealed that cancer cell dissemination is an early step in melanoma progression and disseminated melanoma cells lack typical driver changes, such as BRAF mutations at dissemination, but continue to evolve and acquire them during colony formation in the sentinel lymph node. Having developed a work flow allowing for the first time to combine the precise quantitative assessment of the tumor cell load of patient lymph nodes with functional and molecular analyses of immune cells and disseminated cancer cells (DCCs), our project aims at understanding how tumor-cell intrinsic and microenvironmental factors contribute to outgrowth of DCCs and lymph node colonization. We will investigate changes in the immune microenvironment associated with lymph node colonization and genetic maturation of disseminated cancer cells. As our previous work has implicated the importance of the exosomal pathway for colonizing DCCs, we will investigate its influence on immunosurveillance in more detail. We will utilize cell lines established from lymph node-colonizing DCCs of melanoma patients, characterize their exosomal miRNA and selected protein-content and evaluate their influence on the phenotype and functionality of immune cells. For the cytokines TNF and IFNg, which are produced during an anti-tumoral immune response by immune cells, both inhibitory and tumor-growth promoting effects have been reported. We will therefore investigate their role on growth and survival as a function of the different genetic maturation status of disseminated cancer cells from non-colonized and colonized lymph nodes. In summary, our combined phenotypic and functional analyses of DCCs and immune cells will unravel the rules of lymph node colonization and fundamentally improve our understanding of therapeutic options in the adjuvant therapeutic situation.