Poster Presentation ASDR-AWTRS-MEPSA 2018 Joint Meeting

Inverse regulation of Notch4 and Wnt5a contribute to melanoma plasticity and drug resistance (#67)

Katherine Robbins 1 2 , Heinz Hammerlindl 1 3 , Sabrina Hammerlindl 1 2 , Miles Seidel 1 , Melitta Kitzwoegerer 4 , Ehsan Bonyadi Rad 5 , Nikolas Haass 1 2 , Erik (Rik) Thompson 6 7 , Helmut Schaider 1 2 , Antje Blumenthal 1 2
  1. Faculty of Medicine, The University of Queensland, St Lucia, QUEENSLAND, Australia
  2. The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
  3. The University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Queensland, Australia
  4. Department of Pathology, University Hospital St. Poelten, Poelten, Austria
  5. Department of Orthopedics and Orthopedic Surgery, Medical University Graz, Graz, Austria
  6. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
  7. School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia

Despite recent breakthroughs in the treatment and management of advanced melanoma patients, disease relapse remains a common and poorly understood phenomenon. Notch and Wnt signalling pathways have been frequently reported in the literature to play an important role in melanoma initiation and progression, however, research concerning the crosstalk and regulation between the two in the context of melanoma is deficient. We seek to elucidate the mechanism by which Notch and Wnt pathways interact and contributes to the metastatic potential of melanoma. Our lab recently characterized a novel tumour suppressive function of Notch4 in melanoma. One of epithelial-mesenchymal markers regulated by Notch4 on the transcript level was Wnt5a. We observe that increased expression of Notch4 is associated with decreased Wnt5a, a protein shown to promote melanoma invasion and metastasis by inducing an epithelial-to-mesenchymal transition. Using melanoma cell lines in which we control the expression of Notch4 and Wnt5a, we seek to test the hypothesis that variable regulation of the Notch-4-Wnt5a axis enables phenotypic switching in melanoma. In this project, functional assays, tumour growth, propensity to metastasize, expression in human melanoma tissue samples, and drug sensitivity will be used to evaluate the phenotypic and functional properties of mutant melanoma cell lines expressing Notch4, Wnt5a, or both. Understanding the regulation between Notch4 and Wnt5a and its contribution to melanoma metastases could allow for the development of improved therapeutics that diminish the versatility of melanoma cells by trapping them in an impasse state.