Cell and Experimental Pathology
Wnt5a signaling in malignant melanoma
Academic Dissertation by due permission of the Faculy of Medicine, Lund University, Sweden
to be defended in the lecture hall, Clinical Research Center, Malmö University Hospital, Malmö on Friday December 16th at 1 p.m. for the degree of Doctor of Philosophy, Faculty of Medicine.
Ass. Professor Gunnar Schulte
Department of Physiology and Pharmalogy
The Wnt signaling pathway is highly conserved and crucial during embryonic development. Aberrant Wnt signaling is important in several different disease processes. One such disease process is the development and progression of cancer. Malignant melanoma is a highly aggressive tumor type, in which Wnt signaling is essential. Once a melanoma tumor has spread and formed metastasis, there are few treatment options and the mean 5-year survival rate is less than 5%. Activation of the non-canonical Wnt signaling pathway via Wnt5a has been correlated with increased migration and invasion as well as a poor prognosis in malignant melanoma patients.
In this thesis, we investigate different processes downstream of Wnt5a that can lead to increased aggressiveness of malignant melanoma. Our studies show that the secreted Wnt modulator, SFRP3 is down-regulated in malignant melanoma patients. Using melanocyte and malignant melanoma cell lines, we demonstrate that the down-regulation is due to methylation. Functional studies show that SFRP3 can inhibit Wnt5a signaling and induce a decrease in migration and invasion. Furthermore, by analyzing the effects of Wnt5a on the malignant melanoma proteome, we provide evidence for a cell context dependent reprogramming of cellular metabolism induced by Wnt5a. Activation of Wnt5a signaling in melanoma cell lines resulted in a pro-tumorigenic effect by favoring aerobic glycolysis. Finally, we investigate the relationship between Wnt5a and secreted pro-tumorigenic factors. We found that Wnt5a could activate regulated secretion of IL-6 and VEGF, dependent on cytoskeletal re-arrangements mediated via calcium signaling and Cdc42 activation.
Taken together these data suggests that, in melanoma, an altered Wnt5a signal can induce different pro-tumorigenic effects. This thesis highlights the complexity of Wnt signaling in general and Wnt5a signaling in melanoma in particular and extends our knowledge of the mechanisms behind progression of malignant melanoma.