Abstract
SMAD7 loss negates the need for phenotype switching to promote invasion and metastasis in melanoma.
Major finding: SMAD7 loss negates the need for phenotype switching to promote invasion and metastasis in melanoma.
Concept: Reduction of SMAD7 in the presence of TGFβ factors promotes a proliferative and invasive phenotype.
Impact: Modulation of SMAD7 levels represents a potential therapeutic strategy in melanoma.
Melanoma cells switch between high proliferative/low invasive and low proliferative/high invasive phenotypes, known as “phenotype switching,” to promote metastasis and treatment resistance. The two phenotypes are dependent upon the expression of microphthalmia-associated transcription factor (MITF), which is inversely correlated with the expression of AXL. Tuncer and colleagues investigated the role of the SMAD–TGFβ signaling axis, a known driver of reversible phenotype switching, in melanoma. Analysis of patient RNA-sequencing data from The Cancer Genome Atlas revealed patients with low SMAD7 levels correlated with significantly shorter overall survival, and high SMAD7 expression was identified in the leading invasive edges of melanoma nodules. Knockdown of SMAD7 in melanoma cells resulted in increased levels of pSMAD2/3 and pSMAD1/5/8, suggesting a role for SMAD7 in inhibiting canonical TGFβ signaling, and correlated with an enrichment of epithelial-to-mesenchymal transition, cell–cell adhesion, and cell-cycle pathways. Further, low to no SMAD7 expression in patient samples and cell lines correlated with high expression of both MITF and AXL, and SMAD7 knockdown increased the TGFβ2/NODAL-mediated invasive capacity of melanoma cells, even in the presence of the SMAD pathway activator BMP7 that promotes proliferation. Similarly, in vivo loss of SMAD7 in melanocytic cells activated both canonical SMAD signaling pathways, as observed via an increase in Dct-positive cells that coexpressed pSMAD2/3 and pSMAD1/5/8, and resulted in increased expression of the invasive markers ZEB1, MITF, and AXL. Although there were no significant differences in hyperplastic dermal lesions nor number of skin melanomas compared to controls, Smad7 knockout mice had significantly increased metastases and decreased melanoma-free survival. Taken together, these data show that modulation of TGFβ signaling abrogates the requirement for phenotype switching and suggest that targeting SMAD7lo melanoma may represent an alternative therapeutic strategy to reduce metastasis and proliferation in melanoma.
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