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

Oncogene. 2020 Jul;39(30):5267-5281. doi: 10.1038/s41388-020-1362-9. Epub 2020 Jun 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Doxorubicin / pharmacology
  • Gene Expression Profiling / methods
  • Hippo Signaling Pathway
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / secondary
  • Lung Neoplasms / therapy
  • Melanoma / genetics*
  • Melanoma / pathology
  • Melanoma / therapy
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Signal Transduction / genetics*
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Skin Neoplasms / therapy
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Xenograft Model Antitumor Assays / methods
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Antibiotics, Antineoplastic
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Doxorubicin
  • Protein Serine-Threonine Kinases