Transforming Growth Factor-β/Smad Signaling Inhibits Melanoma Cancer Stem Cell Self-Renewal, Tumor Formation and Metastasis.

Simple Summary: Transforming growth factor-beta (TGFβ) mediates various biological processes including cell growth, cell death, cellular differentiation and stemness, among others. TGFβ also regulates tumor formation and metastasis in a context-dependent manner. This research aims to investigate and define the role of the TGFβ cell signaling pathway in melanoma, which is a deadly form of skin cancer. Using relevant melanoma cancer cell lines and preclinical models of melanoma, we show that TGFβ acts as a potent tumor suppressor and negative regulator of cancer stemness and metastasis in melanoma. These findings will be instrumental for the future development of targeted therapy in melanoma. The secreted protein transforming growth factor-beta (TGFβ) plays essential roles, ranging from cell growth regulation and cell differentiation in both normal and cancer cells. In melanoma, TGFβ acts as a potent tumor suppressor in melanoma by blocking cell cycle progression and inducing apoptosis. In the present study, we found TGFβ to regulate cancer stemness in melanoma through the Smad signaling pathway. We discovered that TGFβ/Smad signaling inhibits melanosphere formation in multiple melanoma cell lines and reduces expression of the CD133+ cancer stem cell subpopulation in a Smad3-dependent manner. Using preclinical models of melanoma, we further showed that preventing Smad3/4 signaling, by means of CRISPR knockouts, promoted both tumorigenesis and lung metastasis in vivo. Collectively, our results define new functions for the TGFβ/Smad signaling axis in melanoma stem-cell maintenance and open avenues for new therapeutic approaches to this disease. [ABSTRACT FROM AUTHOR]