SMAD signaling promotes melanoma metastasis independently of phenotype switching
Eylul Tuncer, … , Reinhard Dummer, Lukas Sommer
Eylul Tuncer, … , Reinhard Dummer, Lukas Sommer
Published April 30, 2019
Citation Information: J Clin Invest. 2019;129(7):2702-2716. https://doi.org/10.1172/JCI94295.
View: Text | PDF
Research Article Cell biology Dermatology Article has an altmetric score of 2

SMAD signaling promotes melanoma metastasis independently of phenotype switching

Abstract

The development of metastatic melanoma is thought to require the dynamic shifting of neoplastic cells between proliferative and invasive phenotypes. Contrary to this conventional “phenotype switching” model, we now show that disease progression can involve malignant melanoma cells simultaneously displaying proliferative and invasive properties. Using a genetic mouse model of melanoma in combination with in vitro analyses of melanoma cell lines, we found that conditional deletion of the downstream signaling molecule Smad4, which abrogates all canonical TGF-β signaling, indeed inhibited both tumor growth and metastasis. Conditional deletion of the inhibitory signaling factor Smad7, however, generated cells that are both highly invasive and proliferative, indicating that invasiveness is compatible with a high proliferation rate. In fact, conditional Smad7 deletion led to sustained melanoma growth and at the same time promoted massive metastasis formation, a result consistent with data indicating that low SMAD7 levels in patient tumors are associated with a poor survival. Our findings reveal that modulation of SMAD7 levels can overcome the need for phenotype switching during tumor progression and may thus represent a therapeutic target in metastatic disease.

Authors

Eylul Tuncer, Raquel R. Calçada, Daniel Zingg, Sandra Varum, Phil Cheng, Sandra N. Freiberger, Chu-Xia Deng, Ingo Kleiter, Mitchell P. Levesque, Reinhard Dummer, Lukas Sommer

×

Figure 7

Loss of Smad7 promotes emergence of proliferative-invasive MITFhiAXLhi melanoma cells in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Loss of Smad7 promotes emergence of proliferative-invasive MITFhiAXLhi m...
(A) Schematic of the melanoma mouse model used to analyze the effect of Smad7 conditional deletion in Tyr::CreERT2 Tyr::NrasQ61K INK4a−/− R26R-LacZ mice. (B) Experimental strategy used to analyze the proliferation rate by EdU injection upon Smad7 loss. (C) Quantification of the number of skin melanomas of control and Smad7-cKO mice (n = 12). (D and E) Immunostaining and quantification of EdU+Zeb1+ cells in Smad7-cKO and control primary tumors (n = 3). Gray and white bars indicate single Zeb1+ and EdU+ cells, respectively. Yellow bars represents percentages of EdU+Zeb1+ cells. White arrowheads in the images indicate EdU+Zeb1+ cells, open arrowheads EdU+Zeb1– cells. (F–H) Quantification and immunostaining of MitfhiAxl+ cells in cKO and control primary tumors. Percentages of MitfhiAxl+ cells calculated over total number of Mitfhi and Mitflo cells (n = 10). Yellow bars represent percentages of Mitfhi cells that are Axl+. White arrowheads indicate MitfhiAxl+ cells, open arrowheads MitfhiAxl– cells. Data are represented as the mean ± SEM. ***P < 0.001, unpaired Student’s t test (C–F). Epi, epidermis. Scale bars: 50 μm.