PT  - JOURNAL ARTICLE
AU  - Fabiana Lüönd
AU  - Martin Pirkl
AU  - Mizue Hisano
AU  - Vincenzo Prestigiacomo
AU  - Ravi KR Kalathur
AU  - Niko Beerenwinkel
AU  - Gerhard Christofori
TI  - Hierarchy of TGFβ/SMAD, Hippo/YAP/TAZ, and Wnt/β-catenin signaling in melanoma phenotype switching
AID  - 10.26508/lsa.202101010
DP  - 2022 Feb 01
TA  - Life Science Alliance
PG  - e202101010
VI  - 5
IP  - 2
4099  - https://www.life-science-alliance.org/content/5/2/e202101010.short
4100  - https://www.life-science-alliance.org/content/5/2/e202101010.full
SO  - Life Sci. Alliance2022 Feb 01; 5
AB  - 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.