The metastatic microenvironment: Claudin-1 suppresses the malignant phenotype of melanoma brain metastasis

Brain metastases occur frequently in melanoma patients with advanced disease whereby the prognosis is dismal. The underlying mechanisms of melanoma brain metastasis development are not well understood. Identification of molecular determinants regulating melanoma brain metastasis would advance the development of prevention and therapy strategies for this disease. Gene expression profiles of cutaneous and brain-metastasizing melanoma variants from three xenograft tumor models established in our laboratory revealed that expression of tight junction component CLDN1 was lower in the brain-metastasizing variants than in cutaneous variants from the same melanoma. The objective of our study was to determine the significance of CLDN1 downregulation/loss in metastatic melanoma and its role in melanoma brain metastasis. An immunohistochemical analysis of human cells of the melanocyte lineage indicated a significant CLDN1 downregulation in metastatic melanomas. Transduction of melanoma brain metastatic cells expressing low levels of CLDN1 with a CLDN1 retrovirus suppressed their metastatic phenotype. CLDN1-overexpressing melanoma cells expressed a lower ability to migrate and adhere to extracellular matrix, reduced tumor aggressiveness in nude mice and, most importantly, eliminated the formation of micrometastases in the brain. In sharp contrast, the ability of the CLDN1-overexpressing cells to form lung micrometastases was not impaired. CLDN1-mediated interactions between these cells and brain endothelial cells constitute the mechanism underlying these results. Taken together, we demonstrated that downregulation or loss of CLDN1 supports the formation of melanoma brain metastasis, and that CLDN1 expression could be a useful prognostic predictor for melanoma patients with a high risk of brain metastasis. What's new? Melanoma often metastasizes to the brain, but if researchers could find out how it does so, perhaps they could prevent it. Cells poised to metastasize often reveal themselves by molecular clues, and indeed, melanoma cells likely to infiltrate the brain express less of the tight-junction protein CLDN1 than other melanoma cells. In this study, the authors showed that when melanoma cells express extra CLDN1, they could not form micro-metastases in the brain - though their ability to metastasize to the lungs was not impaired. Thus, CLDN1 expression could help predict the likelihood of brain metastasis, and targeting cells expressing low levels of the protein could help prevent or treat this deadly complication.