YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression

Cell Rep. 2019 Dec 3;29(10):3200-3211.e4. doi: 10.1016/j.celrep.2019.03.021.


Uveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations. Hippo/YAP and Ras/mitogen-activated protein kinase (MAPK) emerge as two important signaling pathways downstream of G protein alpha subunits of the Q class (GαQ/11)-mediated transformation, although whether and how they contribute to UM genesis in vivo remain unclear. Here, we adapt an adeno-associated virus (AAV)-based ocular injection method to directly deliver Cre recombinase into the mouse uveal tract and demonstrate that Lats1/2 kinases suppress UM formation specifically in uveal melanocytes. We find that genetic activation of YAP, but not Kras, is sufficient to initiate UM. We show that YAP/TAZ activation induced by Lats1/2 deletion cooperates with Kras to promote UM progression via downstream transcriptional reinforcement. Furthermore, dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress oncogenic growth of human UM cells. Our data highlight the functional significance of Lats-YAP/TAZ in UM initiation and progression in vivo and suggest combination inhibition of YAP/TAZ and Ras/MAPK as a new therapeutic strategy for UM.

Keywords: AAV ocular injection; Hippo/YAP; Ras/MAPK; dual inhibition; mouse model; tumor initiation; tumor progression; uveal melanoma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Cell Cycle Proteins / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Disease Progression
  • Female
  • HEK293 Cells
  • Humans
  • Melanocytes / pathology
  • Melanoma / genetics*
  • Melanoma / pathology*
  • Mice
  • Mitogen-Activated Protein Kinases / genetics
  • Mutation / genetics
  • Signal Transduction / genetics
  • Trans-Activators / genetics*
  • Transcription Factors / genetics*
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Uveal Neoplasms / genetics*
  • Uveal Neoplasms / pathology*
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human
  • Wwtr1 protein, mouse
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Yap1 protein, mouse
  • Mitogen-Activated Protein Kinases

Supplementary concepts

  • Uveal melanoma