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.
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Research Article Cell biology Dermatology

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

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Figure 4

Low SMAD7 levels are associated with altered cell adhesion and cell cycle programs in human melanoma cell lines.

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Low SMAD7 levels are associated with altered cell adhesion and cell cycl...
(A) Heatmap showing genes differentially expressed in SMAD7 knockdown and control M010817 cells (3557 genes, row z-score from 3 replicate RNA-Seq experiments). The gene list was generated using a 1.5-fold-change cut-off, and a P value of 0.05. Of these, 1586 were upregulated and 1971 downregulated. (B) GO analysis based on differentially regulated genes upon SMAD7 knockdown. Each individual node shows an enriched GO term (P < 0.05) (Corrected with Bonferroni’s step down procedure). BP, biological process; MF, molecular function; CC, cellular component. A fully labeled version is given in Supplemental Figure 4F. (C) Venn diagram shows the upregulated and downregulated common genes involved in previously described Verfaillie invasive (Inv.) and proliferative (Pro.) program. (D) Heatmap of differentially expressed genes associated with Verfaillie invasive and proliferative programs (proliferative program, n = 165/627, invasive program. n = 203/695) (44) Red, increased; blue, decreased expression. (E and G) Venn diagram showing the overlap between MITFhi and AXLhi gene expression programs derived from patient melanoma samples obtained by single-cell RNA sequencing (16) with genes changed between low/high expressing SMAD7 patients or upon siRNA-mediated knockdown of SMAD7 in M010817. (F and H) Heatmaps indicate differentially expressed MITF and AXL program genes, respectively. For gene lists corresponding to D, F, and H, see Supplemental Tables 3 and 4, respectively.