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Abstract

Cutaneous melanoma arises from melanocytes in the skin and is a highly aggressive cancer that metastasizes early and has a poor prognosis. In recent years treatment of malignant melanoma has been revolutionized by the introduction of immune checkpoint inhibition (ICI) and targeted therapies. However, not all patients have the same prognosis and benefit from immunotherapy. Especially patients with liver metastases are associated with a poor prognosis and a poor response to ICI and targeted therapy of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutated melanoma. In 1889 Stephen Paget postulated in the „seed and soil “-hypothesis that circulating tumor cells are homed to selected sites. And indeed, melanoma metastasis is remarkably organ specific (organotropism). Organotropism can be explained by tumor cell intrinsic factors and by microenvironmental, organ-specific cues. In the organ-specific niche endothelial cells (EC) build the first line of contact for circulating tumor cells. The vascular niche might favor or suppress tumor cell arrest and extravasation. The vascular niche in the liver is composed of liver sinusoidal endothelial cells (LSEC). LSEC form a sinusoidal discontinuous endothelium that lacks a basement membrane and contains fenestrations without diaphragms. In this thesis I analyzed the organ-specific, endothelial-dependent mechanisms as well as tumor intrinsic mechanisms of malignant melanoma cell dissemination to the liver. In an experimental liver colonization model the hematogenous spread of tumor cells was mimicked. Murine melanoma cell lines, heterogenous in their underlying driver mutations, were injected into the spleen of C57BL/6 mice to induce liver metastasis. Additionally, the melanoma cell line WT31 harboring a human neuroblastoma Ras viral oncogene homolog (Nras) mutation was injected into the tail vein leading amongst other organs to liver colonization. Melanoma cell lines differed in their metastatic efficiency and high and intermediate metastatic melanoma cell lines were further analyzed. A common histopathological growth pattern of the high and intermediate metastatic melanoma cell lines was identified. Although, these cell lines differed in their vascular density, tumor endothelial cells shared a common expression profile. In the second part of my thesis, the influence of notch overexpression in hepatic endothelial cells (HEC) using genetically modified NICDOE-HEC mice was studied. Notch 1 intracellular domain (NICD) overexpression in HEC significantly protected from liver metastasis in two models of malignant melanoma and in a model of colorectal cancer. Further, alterations in endothelial and metabolic zonation were detected and the expression of adhesion molecules was altered in NICDOE-HEC mice. Downregulation of intercellular adhesion molecule 1 (ICAM1) was identified as a potential mechanism of protection from liver metastasis in NICDOE-HEC mice.