Hierarchy of TGFβ/SMAD, Hippo/YAP/TAZ, and Wnt/β-catenin signaling in melanoma phenotype switching

Abstract

In melanoma, a switch from a proliferative melanocytic to an invasive mesenchymal phenotype is based on dramatic transcriptional reprogramming which involves complex interactions between a variety of signaling pathways and their downstream transcriptional regulators. TGFβ/SMAD, Hippo/YAP/TAZ, and Wnt/β-catenin signaling pathways are major inducers of transcriptional reprogramming and converge at several levels. Here, we report that TGFβ/SMAD, YAP/TAZ, and β-catenin are all required for a proliferative-to-invasive phenotype switch. Loss and gain of function experimentation, global gene expression analysis, and computational nested effects models revealed the hierarchy between these signaling pathways and identified shared target genes. SMAD-mediated transcription at the top of the hierarchy leads to the activation of YAP/TAZ and of β-catenin, with YAP/TAZ governing an essential subprogram of TGFβ-induced phenotype switching. Wnt/β-catenin signaling is situated further downstream and exerts a dual role: it promotes the proliferative, differentiated melanoma cell phenotype and it is essential but not sufficient for SMAD or YAP/TAZ–induced phenotype switching. The results identify epistatic interactions among the signaling pathways underlying melanoma phenotype switching and highlight the priorities in targets for melanoma therapy.

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

“…Phenotype switching refers to the switch from a proliferative to an invasive phenotype, conferring plasticity to cancer cells. The switch implicates transcriptional reprogramming involving a panoply of signaling pathways with their respective downstream regulators including TGFβ/SMADs, Hippo/TAP/TAZ and Wnt/B-catenin [ 58 ]. Furthermore, MITF (microphthalmia-associated transcription factor) is an important melanocytic lineage-specific transcription factor also associated with phenotype switching.…”

TGF-β Type I Receptor Signaling in Melanoma Liver Metastases Increases Metastatic Outgrowth

“…Dedifferentiation of melanoma cells, resulting in depigmentation and migration of the tumor cells, is known to be promoted by TGF-β in vitro and in vivo [38]. Crosstalk with other pathways can contribute to the rewiring to TGF-β stimulation as well [39]. Additionally, behavior of B16 cells upon TGF-β treatment could be matrix dependent, as an increase of migration was observed in vitro in different collagen-based matrixes [12,38].…”

The role of yes activated protein (YAP) in melanoma metastasis

“… 58 , 59 , 60 , 61 , 62 Indeed, recent experiments using human cancer cell lines suggest that TGFβ/SMAD and YAP/TAZ promote an invasive, whereas canonical Wnt signaling promotes a proliferative, phenotype switch. 63 This invasive phenotype includes increased expression of a YAP/TGFβ signature including elevated CCN1 and CCN2 production and reduced expression of MITF 63 ( Figure 2 ). Thus, the YAP/hippo pathway, in concert with TGFβ production is highly implicated in initiating the invasive melanoma phenotype.…”