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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Smad7 restricts melanoma invasion by restoring N-cadherin expression and establishing heterotypic cell-cell
Kyle A DiVito1, Valerie A Trabosh, You-Shin Chen
1Department of Biochemistry & Molecular Biology, Georgetown University School of Medicine Washington, DC, USA.
Abstract:
The list of transforming growth factor-beta (TGF-β)-related proteins in non-canonical TGF-β signaling is growing. Examples include receptor-Smads directing micro-RNA processing and inhibitory-Smads, e.g. Smad7, directing cell adhesion. Human skin grafts with fluorescently tagged melanoma cells revealed Smad7-expressing cells positioned themselves proximal to the dermal-epidermal junction and failed to form tumors, while control cells readily invaded and formed tumors within the dermis. Smad7 significantly inhibited β-catenin T41/S45 phosphorylation associated with degradation and induced a 4.5-fold increase in full-length N-cadherin. Cell adhesion assays confirmed a strong interaction between Smad7-expressing cells and primary dermal fibroblasts mediated via N-cadherin, while control cells were incapable of such interaction. Immunofluorescent analysis of skin grafts indicated N-cadherin homotypic interaction at the surface of both Smad7 cells and primary dermal fibroblasts, in contrast to control melanoma cells. We propose that Smad7 suppresses β-catenin degradation and promotes interaction with N-cadherin, stabilizing association with neighboring dermal fibroblasts, thus mitigating invasion.
Insights
Smad7 protein prevents melanoma invasion in human skin grafts by inhibiting beta-catenin degradation and promoting N-cadherin cell adhesion. This finding offers new insights into non-canonical TGF-β signaling in cancer progression.
Area of Science:
- Cell biology
- Cancer research
- Dermatology
Background:
- Non-canonical transforming growth factor-beta (TGF-β) signaling involves diverse proteins influencing cellular processes.
- Inhibitory-Smads, such as Smad7, play roles in regulating cell adhesion and behavior.
- Melanoma invasion is a critical factor in cancer progression and metastasis.
Purpose of the Study:
- To investigate the role of Smad7 in melanoma cell invasion and tumor formation in human skin grafts.
- To elucidate the molecular mechanisms by which Smad7 affects cell adhesion and beta-catenin signaling.
Main Methods:
- Utilized human skin graft models with fluorescently tagged melanoma cells.
- Assessed Smad7 expression, beta-catenin phosphorylation, and N-cadherin levels.
- Performed cell adhesion assays and immunofluorescent analysis.
Main Results:
- Smad7-expressing melanoma cells localized near the dermal-epidermal junction and did not form tumors.
- Control melanoma cells readily invaded the dermis and formed tumors.
- Smad7 inhibited beta-catenin phosphorylation and increased full-length N-cadherin.
- Smad7 promoted N-cadherin-mediated adhesion between melanoma cells and dermal fibroblasts.
Conclusions:
- Smad7 suppresses melanoma invasion by inhibiting beta-catenin degradation and enhancing N-cadherin-mediated cell adhesion.
- Smad7 stabilizes melanoma cell association with dermal fibroblasts, thereby mitigating invasion.
- These findings highlight Smad7 as a potential therapeutic target for preventing melanoma metastasis.
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