Abstract
Epithelial-to-mesenchymal transition (EMT), in which epithelial cells loose their polarity and become motile mesenchymal cells, is a determinant of melanoma metastasis. We compared gene expression signatures of mesenchymal-like melanoma cells with those of epithelial-like melanoma cells, and identified Thrombospondin 1 (THBS1) as highly up-regulated in the mesenchymal phenotype. This study investigated whether THBS1, a major physiological activator of transforming growth factor (TGF)-beta, is involved in melanoma EMT-like process. We sought to examine expression patterns in distinct melanoma phenotypes including invasive, de-differentiated, label-retaining and drug resistant populations that are putatively associated with an EMT-like process. Here we show that THBS1 expression and secretion was elevated in melanoma cells exhibiting invasive, drug resistant, label retaining and mesenchymal phenotypes and correlated with reduced expression of genes involved in pigmentation. Elevated THBS1 levels were detected in Vemurafenib resistant melanoma cells and inhibition of THBS1 led to significantly reduced chemoresistance in melanoma cells. Notably, siRNA-mediated silencing of THBS1 and neutralizing antibody to THBS1 reduced invasion in mesenchymal-like melanoma cells, while ectopic THBS1 expression in epithelial-like melanoma cells enhanced invasion. Furthermore, the loss of THBS1 inhibited in vivo motility of melanoma cells within the embryonic chicken neural tube. In addition, we found aberrant THBS1 protein expression in metastatic melanoma tumor biopsies. These results implicate a role for THBS1 in EMT, and hence THBS1 may serve as a novel target for strategies aimed at the treatment of melanoma invasion and drug resistance.
Highlights
Melanoma is a frequently fatal malignancy of the neural crest-derived melanocytes, the pigment producing cells in skin, uveal tract and mucosal membranes
We evaluated the expression of classical epithelial-to-mesenchymal transition (EMT) genes, E- and N-cadherins using quantitative real-time RT-PCR in a panel of 54 human melanoma cell lines that were derived from resected melanoma metastases [22]
A gene-set enrichment analysis (GSEA) of the cell lines revealed gene sets associated with transforming growth factor (TGF)-beta signaling [23], cell migration [24, 25], ECM modulation [26] and EMT [27,28,29]
Summary
Melanoma is a frequently fatal malignancy of the neural crest-derived melanocytes, the pigment producing cells in skin, uveal tract and mucosal membranes. EMT describes a reprogramming of epithelial cells that leads to the loss of epithelial characteristics, notably polarity and cell adhesion, and the acquisition of a mesenchymal phenotype with increased invasive abilities. It occurs during normal development as part of processes such as gastrulation and neural crest cell migration [7]. During cancer progression, this phenotype is associated with tumor invasion, metastatic dissemination, and acquisition of resistance to drug treatment [8, 9]. Cadherin switching is a hallmark of EMT, leading to the downregulation and replacement of the cell surface adhesion molecule E-cadherin by N-cadherin, enabling motility [10,11,12]
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