Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/12313
Title: Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma.
Austin Authors: Jayachandran, Aparna;Anaka, Matthew;Prithviraj, Prashanth;Hudson, Christopher;McKeown, Sonja J;Lo, Pu-Han;Vella, Laura J;Goding, Colin R;Cebon, Jonathan S ;Behren, Andreas
Affiliation: Ludwig Institute for Cancer Research, University of Oxford, Oxford, OX3 7DQ, UK
Department of Anatomy and Neuroscience, University of Melbourne, Victoria, 3010, Australia
Department of Medicine, University of Melbourne, Victoria, 3010, Australia
Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC 3084, Australia
Issue Date: 30-Jul-2014
Publication information: Oncotarget; 5(14): 5782-97
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.
Gov't Doc #: 25051363
URI: http://ahro.austin.org.au/austinjspui/handle/1/12313
URL: https://pubmed.ncbi.nlm.nih.gov/25051363
Type: Journal Article
Appears in Collections:Journal articles

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