Abstract
We previously identified the chemokine receptor CCR4 as part of the molecular signature of melanoma brain metastasis. The aim of this study was to determine the functional significance of CCR4 in melanoma brain metastasis. We show that CCR4 is more highly expressed by brain metastasizing melanoma cells than by local cutaneous cells from the same melanoma. Moreover, we found that the expression of CCR4 is significantly higher in paired clinical specimens of melanoma metastases than in samples of primary tumors from the same patients. Notably, the expression of the CCR4 ligands, Ccl22 and Ccl17 is upregulated at the earliest stages of brain metastasis, and precedes the infiltration of melanoma cells to the brain. In-vitro, CCL17 induced migration and transendothelial migration of melanoma cells. Functionally, human melanoma cells over-expressing CCR4 were more tumorigenic and produced a higher load of spontaneous brain micrometastasis than control cells. Blocking CCR4 with a small molecule CCR4 antagonist in-vivo, reduced the tumorigenicity and micrometastasis formation of melanoma cells. Taken together, these findings implicate CCR4 as a driver of melanoma brain metastasis.
Highlights
It is well established that interactions between tumor cells with non-tumor cells in the tumor microenvironment drive tumor progression towards metastasis [1,2,3]
Our previous results have indicated that the chemokine receptor Chemokine receptor 4 (CCR4) is significantly upregulated in brain-metastasizing melanoma cells [6]
We evaluated the expression of CCR4 in a panel of three patient-derived cell lines of melanoma brain metastasis (MBM) (YDFR, UCLA-SO-M12, and UCLA-SO-M16)
Summary
It is well established that interactions between tumor cells with non-tumor cells in the tumor microenvironment drive tumor progression towards metastasis [1,2,3]. Determinants of metastasis are cells or molecules whose activity is required for the targeted migration of metastasizing tumor cells to the secondary target organ and for their survival and propagation within this organ. To identify and characterize determinants of metastasis we developed human to mouse xenograft models comprising non-metastatic and metastatic variants originating in the same human neuroblastoma or melanoma [4,5,6] tumors. Since these variants have identical genetic backgrounds, transcriptomic, proteomic, genomic and epigenomic differences between nonmetastatic and metastatic variants can be attributed to differences between their metastatic phenotypes. We established a molecular signature of melanoma brain metastasis (MBM) including among others, the chemokine receptor CCR4 [5, 6] and the tight junction protein Claudin-1 [7]
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