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.
Highlights
Melanoma arising by transformation of melanocytes is one of the most aggressive and deadliest cancers
We treated proliferative M000921 and M010817 patient-derived melanoma cells (Hoek et al, 2006) with either recombinant human TGFβ or with recombinant murine Wnt-3a, or we knocked down LATS1 and LATS2 to induce the transcriptional activity of YAP/TAZ
Using in vitro perturbation studies, global gene expression analysis, and Nested effects models (NEMs) computation, we revealed the hierarchy of three major signaling pathways converging to each other during melanoma phenotype switching
Summary
Melanoma arising by transformation of melanocytes is one of the most aggressive and deadliest cancers. To describe the malignant progression of melanoma from benign horizontal growth to invasive cancer and metastasis formation, a melanoma phenotype switching model has been proposed. While the existence of intermediate states during melanoma phenotype switching has recently been reported (Tirosh et al, 2016; Tsoi et al, 2018; Rambow et al, 2019; Tuncer et al, 2019; Wouters et al, 2020), less is known about the crosstalk and hierarchy of signaling pathways inducing a proliferative-to-invasive phenotype switch
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
