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// Sivan Izraely 1 , Shlomit Ben-Menachem 1 , Orit Sagi-Assif 1 , Tsipi Meshel 1 , Diego M. Marzese 2 , Shuichi Ohe 2 , Inna Zubrilov 1 , Metsada Pasmanik-Chor 3 , Dave S.B. Hoon 2 and Isaac P. Witz 1 1 Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel 2 Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, USA 3 Bioinformatics Unit, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel Correspondence to: Isaac P. Witz, email: // Keywords : ANGPTL4, melanoma, brain, metastasis, TGFβ1 Received : March 15, 2017 Accepted : June 10, 2017 Published : July 05, 2017 Abstract In an ongoing effort to identify molecular determinants regulating melanoma brain metastasis, we previously identified Angiopoietin-like 4 (ANGPTL4) as a component of the molecular signature of such metastases. The aim of this study was to determine the functional significance of ANGPTL4 in the shaping of melanoma malignancy phenotype, especially in the establishment of brain metastasis. We confirmed that ANGPTL4 expression is significantly higher in cells metastasizing to the brain than in cells from the cutaneous (local) tumor from the same melanoma in a nude mouse xenograft model, and also in paired clinical specimens of melanoma metastases than in primary melanomas from the same patients. In vitro experiments indicated that brain-derived soluble factors and transforming growth factor β1 (TGFβ1) up-regulated ANGPTL4 expression by melanoma cells. Forced over-expression of ANGPTL4 in cutaneous melanoma cells promoted their ability to adhere and transmigrate brain endothelial cells. Over-expressing ANGPTL4 in cells derived from brain metastases resulted in the opposite effects. In vivo data indicated that forced overexpression of ANGPTL4 promoted the tumorigenicity of cutaneous melanoma cells but did not increase their ability to form brain metastasis. This finding can be explained by inhibitory activities of brain-derived soluble factors. Taken together these findings indicate that ANGPTL4 promotes the malignancy phenotype of primary melanomas of risk to metastasize to the brain.