Research Papers:

Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma

Aparna Jayachandran _, Matthew Anaka, Prashanth Prithviraj, Christopher Hudson, Sonja J. McKeown, Pu-Han Lo, Laura J. Vella, Colin R. Goding, Jonathan Cebon and Andreas Behren

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Oncotarget. 2014; 5:5782-5797. https://doi.org/10.18632/oncotarget.2164

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Aparna Jayachandran1,2, Matthew Anaka1,2, Prashanth Prithviraj1,2, Christopher Hudson1, Sonja J McKeown3, Pu-Han Lo1, Laura J Vella1,2, Colin R Goding4, Jonathan Cebon1,2, Andreas Behren1,2

1 Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC 3084, Australia.

2 Department of Medicine, University of Melbourne, Victoria, 3010, Australia

3 Department of Anatomy and Neuroscience, University of Melbourne, Victoria, 3010, Australia

4 Ludwig Institute for Cancer Research, University of Oxford, Oxford, OX3 7DQ, UK

Correspondence to:

Andreas Behren, e-mail: [email protected]

Keywords: Thrombospondin 1, melanoma, epithelial-to-mesenchymal transition, chick embryo, invasion, drug resistance

Received: April 29, 2014     Accepted:June 23, 2014     Published: July 08, 2014


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.

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