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The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis

Abstract

Melanoma is a deadly form of skin cancer that accounts for a disproportionally large proportion of cancer-related deaths in younger people. Compared with most other skin cancers, a feature of melanoma is its high metastatic capacity, although the mechanisms that confer this are not well understood. The Hippo pathway is a key regulator of organ growth and cell fate that is deregulated in many cancers. To analyse the Hippo pathway in cutaneous melanoma, we generated a transcriptional signature of melanoma cells that overexpressed YAP, the key downstream Hippo pathway oncoprotein. YAP-mediated transcriptional activity varied in melanoma cell lines but did not cluster with known genetic drivers of melanomagenesis such as BRAF and NRAS mutations. Instead, it correlated strongly with published gene expression profiles linked to melanoma cell invasiveness and varied throughout the metastatic cascade in melanoma patient tumours. Consistent with this, YAP was both necessary and sufficient for melanoma cell invasion in vitro. In vivo, YAP promoted spontaneous melanoma metastasis, whilst the growth of YAP-expressing primary tumours was impeded. Finally, we identified the YAP target genes AXL, THBS1 and CYR61 as key mediators of YAP-induced melanoma cell invasion. These data suggest that YAP is a critical regulator of melanoma metastasis.

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Fig. 1: YAP activity is elevated in invasive melanoma cell lines.
Fig. 2: YAP can induce invasion in normally non-invasive melanoma cells.
Fig. 3: YAP is required for the invasive ability of melanoma cells.
Fig. 4: YAP induces spontaneous melanoma metastasis in vivo and hinders primary tumour growth.
Fig. 5: YAP induces spontaneous melanoma metastasis in vivo.
Fig. 6: Identification of YAP target genes that mediate its ability to stimulate melanoma cell invasion.
Fig. 7: The YAP target genes AXL, THBS1 and CYR61 are required for melanoma cell invasion.

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Acknowledgements

We thank the following Peter MacCallum Cancer Centre core facilities: Molecular Genomics, Bioinformatics, Flow Cytometry and the Centre for Advanced Histology and Microscopy, which were in part supported by the Australian Cancer Research Foundation. KFH was supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (APP1078220). MS was supported by Pfizer Australia, NHMRC, veski, and VCA Fellowships. This research was supported by grants from the Cancer Council of Victoria (APP1080255) and NHMRC (APP1145166), and by the Peter MacCallum Cancer Foundation. ATP was supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (APP1116955) and by the Lorenzo and Pamela Galli Charitable Trust. The research benefitted by support from the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure Support. LY was supported by the China Scholarship Council. AK was supported by an Australian Government Research Training Programme Scholarship and a Rosie Lew Peter MacCallum Cancer Foundation Postgraduate Award.

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Zhang, X., Yang, L., Szeto, P. et al. The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis. Oncogene 39, 5267–5281 (2020). https://doi.org/10.1038/s41388-020-1362-9

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