SPARC Represses E-Cadherin and Induces Mesenchymal Transition during Melanoma Development

Abstract

During progression of melanoma, loss of the cell-cell adhesion molecule E-cadherin contributes to uncontrolled growth and invasive behavior of transformed melanocytes. Secreted protein acidic and rich in cysteine (SPARC) is a nonstructural matricellular protein that regulates cell-matrix interactions leading to alterations in cell adhesion and proliferation. Overexpression of SPARC has been associated with progression of various cancers, including melanoma; however, its role in primary tumor development is not well defined. We show that normal human melanocytes overexpressing SPARC adopt a fibroblastlike morphology, concomitant with loss of E-cadherin and Pcadherin expression, and increased expression of mesenchymal markers. Concurrent with these changes, SPARC expression stimulates melanocyte motility and melanoma cell invasion. Expression of SPARC results in transcriptional down-regulation of E-cadherin that correlates with induction of Snail, a repressor of E-cadherin. Conversely, SPARC depletion leads to up-regulation of E-cadherin and reduces Snail levels, and SPARC-null cells exhibit a marked change in their mesenchymal phenotype. Finally, analysis of SPARC, Snail, and E-cadherin levels in melanocytes and malignant melanoma cell lines further supports the functional relationship among these proteins during melanoma progression. Our findings provide evidence for the role of SPARC in early transformation of melanocytes and identify a novel mechanism, whereby tumor-derived SPARC promotes tumorigenesis by mediating Snail induction and E-cadherin suppression. (Cancer Res 2006; 66(15): 7516-23)

Scattering of Cell Clusters in Confinement

“…3 d). Thus, the CE adhesions and the CC junctions have an antagonistic relationship, consistent with previous experimental findings of integrincadherin crosstalk (19,30). The reduced stabilization of CEs in softer ECMs caused low protrusion and actomyosin forces, which in turn disabled the dissociation rate of CC junctions.…”

Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis

“…In the tumour microenvironment, both neoplastic and neighbouring stromal cells can produce SPARC, thereby imparting a complexity of action for SPARC in cancer. In melanoma, we and others have previously identified an autocrine role for SPARC in regulating invasiveness, epithelial-mesenchymal-like transition and melanoma survival [14][15][16]42 . Although SPARC expression has been clearly linked to cancer progression through cell-autonomous and non-autonomous actions in cell invasion and survival 20,43,44 , its function as a paracrine factor has remained poorly characterized.…”

“…We identify the matricellular SPARC protein, as a critical tumour-secreted permeability factor and a novel paracrine mediator of endothelium permeability during melanoma metastatic dissemination to lungs. Abnormal expression of SPARC has been reported in various cancer cell types including melanoma 13 , in which SPARC was shown to play a key role in melanoma cell tumorigenicity [14][15][16] . However, its role as a paracrine mediator of haematogenous metastasis during extravasation remains unclear.…”

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…Inflammatory factors present in the TME, including TGF-β and IL-1β, lead to increased invasion and metastasis in melanoma, glioma and NSCLC [95][96][97]. These inflammatory mediators are present early in the TME.…”

“…Expression of SPARC in tumor cells, CAFs and stromal endothelial cells can lead to an EMT-like phenotype, including loss of cell-cell adhesion and induction of MMPs and has been shown to increase tumorigenicity [110][111][112]. Expression of SPARC in the tumor stroma is correlated independently with poor prognosis and increased mortality in NSCLC and pancreatic cancers [113,114] and leads to increased invasion and metastasis in melanoma, glioma and NSCLC [95][96][97]115]. Tumor-associated macrophages recruited to the inflammatory microenvironment also secrete SPARC [116].…”