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

Robert, Guillaume; Gaggioli, Cédric; Bailet, Olivier; Chavey, Carine; Abbe, Patricia; Aberdam, Édith; Sabatié, Emilie; Cano, Amparo; Herreros, Antonio Garcı́a de; Ballotti, Robert; Tartare‐Deckert, Sophie

doi:10.1158/0008-5472.can-05-3189

Cited by 145 publications

(169 citation statements)

References 46 publications

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“…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.…”

Section: Resultssupporting

confidence: 89%

Scattering of Cell Clusters in Confinement

Pathak

2016

Biophysical Journal

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Epithelial-to-mesenchymal transition (EMT) enables scattering of cell clusters and disseminates motile cells to distant locations in vivo during embryonic development and cancer metastasis. Both stiffness and topography of the extracellular matrix (ECM) have been shown to influence EMT. In this work, we examine how the integrity of epithelial cell clusters is regulated by subcellular forces, protrusions, and adhesions for varying ECM inputs, such as stiffness, topography, and dimensionality. Our model simulates multicell networks of defined sizes and shapes in ECMs of varied stiffness and geometry. The integrity of cell clusters is dictated by cell-cell junctions, which depend on subcellular forces and adhesion dynamics within each cell of the cluster. Our simulations demonstrate an enhanced dissociation of cell-cell junctions in stiffer and more confined three-dimensional (3D) environments, consistent with experimental findings. In narrow channels, the cell edges parallel to the axis of channels lose their cell-cell junctions more readily than those oriented in the perpendicular direction. The inhibition of protrusive activity and cell polarity disables confinement-dependent cell scattering. Here, cell adhesion and spreading along channel walls is found to be essential for scattering. The model also predicts that two-dimensional (2D) confinement of clusters restricts cell spreading and simultaneously blunts the confinement-sensitive cell scattering. This new, to our knowledge, multiscale model integrates molecular adhesion dynamics, subcellular forces, cellular deformation, and macroscale mechanical properties of the ECM to predict the state of cell clusters of defined shapes and sizes. The predictions made by our model not only match experimental findings from a number of experimental setups, but also provide a new conceptual framework for understanding mechanosensitive cell scattering and EMT.

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Section: Resultssupporting

confidence: 89%

Scattering of Cell Clusters in Confinement

Pathak

2016

Biophysical Journal

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“…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.…”

Section: Discussionmentioning

confidence: 85%

“…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.…”

mentioning

confidence: 99%

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

et al. 2015

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Disruption of the endothelial barrier by tumour-derived secreted factors is a critical step in cancer cell extravasation and metastasis. Here, by comparative proteomic analysis of melanoma secretomes, we identify the matricellular protein SPARC as a novel tumour-derived vascular permeability factor. SPARC deficiency abrogates tumour-initiated permeability of lung capillaries and prevents extravasation, whereas SPARC overexpression enhances vascular leakiness, extravasation and lung metastasis. SPARC-induced paracellular permeability is dependent on the endothelial VCAM1 receptor and p38 MAPK signalling. Blocking VCAM1 impedes melanoma-induced endothelial permeability and extravasation. The clinical relevance of our findings is highlighted by high levels of SPARC detected in tumour from human pulmonary melanoma lesions. Our study establishes tumour-produced SPARC and VCAM1 as regulators of cancer extravasation, revealing a novel targetable interaction for prevention of metastasis.

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“…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.…”

Section: Inflammation In the Tme Drives Invasionmentioning

confidence: 99%

“…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].…”

Section: Inflammation In the Tme Drives Invasionmentioning

confidence: 99%

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

Heinrich

Walser

Krysan

et al. 2011

Cancer Microenvironment

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The inflammatory tumor microenvironment (TME) has many roles in tumor progression and metastasis, including creation of a hypoxic environment, increased angiogenesis and invasion, changes in expression of microRNAs (miRNAs) and an increase in a stem cell phenotype. Each of these has an impact on epithelial mesenchymal transition (EMT), particularly through the downregulation of E-cadherin. Here we review seminal work and recent findings linking the role of inflammation in the TME, EMT and lung cancer initiation, progression and metastasis.Finally, we discuss the potential of targeting aspects of inflammation and EMT in cancer prevention and treatment.

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

Cited by 145 publications

References 46 publications

Scattering of Cell Clusters in Confinement

Scattering of Cell Clusters in Confinement

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

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

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