title: Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma.
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.
authors: Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC 3084, Australia. Department of Medicine, University of Melbourne, Victoria, 3010, Australia.
authors: Aparna
authors: A
authors: Jayachandran
authors: Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC 3084, Australia. Department of Medicine, University of Melbourne, Victoria, 3010, Australia.
authors: Matthew
authors: M
authors: Anaka
authors: Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC 3084, Australia. Department of Medicine, University of Melbourne, Victoria, 3010, Australia.
authors: Prashanth
authors: P
authors: Prithviraj
authors: Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC 3084, Australia.
authors: Christopher
authors: C
authors: Hudson
authors: Department of Anatomy and Neuroscience, University of Melbourne, Victoria, 3010, Australia.
authors: Sonja J
authors: SJ
authors: McKeown
authors: Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC 3084, Australia.
authors: Pu-Han
authors: PH
authors: Lo
authors: Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC 3084, Australia. Department of Medicine, University of Melbourne, Victoria, 3010, Australia.
authors: Laura J
authors: LJ
authors: Vella
authors: Ludwig Institute for Cancer Research, University of Oxford, Oxford, OX3 7DQ, UK.
authors: Colin R
authors: CR
authors: Goding
authors: Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC 3084, Australia. Department of Medicine, University of Melbourne, Victoria, 3010, Australia.
authors: Jonathan
authors: J
authors: Cebon
authors: Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC 3084, Australia. Department of Medicine, University of Melbourne, Victoria, 3010, Australia.
authors: Andreas
authors: A
authors: Behren
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010641:Phenotype; D019700:Thrombospondin 1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: D019700:Thrombospondin 1