Poster Presentation Australasian Melanoma Conference 2018

The control of melanoma metastasis by the YAP oncogene (#128)

Lie Yang 1 2 3 , Xiaomeng Zhang 1 2 , Pacman Szeto 4 5 , Youfang Zhang 4 5 , Mark Shackleton 4 5 , Kieran F. Harvey 1 2 5
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  3. School of Medicine, Tsinghua University, Beijing, China
  4. Department of Oncology, Alfred Hospital, Melbourne, VIC, Australia
  5. Monash University, Melbourne, VIC, Australia

Malignant melanoma is an aggressive cancer with a poor prognosis once it has metastasized. Patients diagnosed only with early stage melanoma have high survival rates, whereas patients with metastatic melanoma have poor survival1. As the mechanisms that drive melanoma progression and metastasis remain inadequately understood, there is an urgent need to understand them towards finding new therapies.

The Hippo pathway is an important regulator of developmental organ growth. Its deregulation stimulates activity of the YAP oncoprotein, which is related to several human cancers5. YAP promotes cancer metastasis3, and its inhibition was reported to reduce melanoma cell invasion in vitro and lung metastasis in vivo following tail vein injection2,4. As the role of YAP in metastasis is not thoroughly understood, we examined the function of an active YAP mutant (YAP-5SA) in cultured cells and melanoma xenograft models.

Melanoma cells stably expressing YAP-5SA showed greater invasive ability in transwell assays. To investigate metastasis in vivo, we used a spontaneous metastasis model by subcutaneously injecting melanoma cells into mice. YAP-5SA expression enhanced vascularity in and metastasis from subcutaneous tumours grown from these injections, even though viability and growth rate in tumours were reduced. This suggests an ability of YAP to promote melanoma metastasis independently of tumour growth. To elucidate YAP-regulated genes that drive melanoma cell invasion, we identified by RNA sequencing a panel of genes that is modulated by YAP. Several of these were important for cell invasion in vitro. Understanding mechanisms by which YAP stimulates melanoma metastasis will help identify more effective therapies for this disease.

  1. Gershenwald, J. E. et al., 2017. ‘Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual’, CA: A Cancer Journal for Clinicians, 67(6), pp. 472–492.
  2. Nallet-Staub, F. et al., 2014. ‘Pro-invasive activity of the hippo pathway effectors YAP and TAZ in cutaneous melanoma’, Journal of Investigative Dermatology, 134(1), pp. 123–132.
  3. Warren, J., Xiao, Y. and Lamar, J., 2018. ‘YAP/TAZ Activation as a Target for Treating Metastatic Cancer’, Cancers, 10(4), p. 115.
  4. Xiong, H. et al., 2017. ‘Yes-Associated Protein (YAP) Promotes Tumorigenesis in Melanoma Cells Through Stimulation of Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1)’, Scientific Reports, 7(1), p. 15528.
  5. Zanconato, F., Cordenonsi, M. and Piccolo, S., 2016. ‘YAP/TAZ at the Roots of Cancer’, Cancer Cell, 29(6), pp. 783–803.