期刊
ONCOGENE
卷 39, 期 30, 页码 5267-5281出版社
SPRINGERNATURE
DOI: 10.1038/s41388-020-1362-9
关键词
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资金
- Australian Cancer Research Foundation
- National Health and Medical Research Council (NHMRC) Senior Research Fellowship [APP1078220, APP1116955]
- Pfizer Australia
- NHMRC [APP1145166]
- veski
- VCA Fellowships
- Cancer Council of Victoria [APP1080255]
- Peter MacCallum Cancer Foundation
- Lorenzo and Pamela Galli Charitable Trust
- Victorian State Government Operational Infrastructure Support
- Australian Government NHMRC Independent Research Institute Infrastructure Support
- China Scholarship Council
- Australian Government Research Training Programme Scholarship
- Rosie Lew Peter MacCallum Cancer Foundation Postgraduate Award
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 asBRAFandNRASmutations. 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 genesAXL,THBS1andCYR61as key mediators of YAP-induced melanoma cell invasion. These data suggest that YAP is a critical regulator of melanoma metastasis.
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