YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression
Huapeng Li,
Qi Li,
Kyvan Dang,
Shan Ma,
Jennifer L. Cotton,
Sun Yang,
Lihua J. Zhu,
April C. Deng,
Y. Tony Ip,
Randy L. Johnson,
Xu Wu,
Claudio Punzo,
Junhao Mao
Affiliations
Huapeng Li
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Qi Li
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
Kyvan Dang
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Shan Ma
Department of Ophthalmology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Neurobiology & Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA
Jennifer L. Cotton
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Sun Yang
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Lihua J. Zhu
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
April C. Deng
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Y. Tony Ip
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
Randy L. Johnson
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Xu Wu
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Claudio Punzo
Department of Ophthalmology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Neurobiology & Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Corresponding author
Junhao Mao
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Corresponding author
Summary: 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. : Li et al. utilize an AAV-based ocular injection method to specifically manipulate Hippo/YAP and Ras signaling in mouse uveal melanocytes. They reveal the role of YAP/TAZ in uveal melanoma formation and suggest that the Hippo/YAP-Ras/MAPK interaction during tumor growth can be exploited to develop a therapeutic strategy for uveal melanoma. Keywords: uveal melanoma, Hippo/YAP, Ras/MAPK, tumor initiation, tumor progression, dual inhibition, mouse model, AAV ocular injection
