Inhibition of WNT5A Signaling and Function in Malignant Melanoma

Abstract: The life-threatening disease of malignant melanoma is one of the fastest growing forms of cancer, affecting an estimated number of 200,000 patients worldwide every year. Although highly curable if detected early, once the melanoma has metastasized there are few treatment options and a median survival rate of only 6-9 months. Consequently, there is an imperative need to identify the factors that drive melanoma metastasis and to develop means of interfering with their actions. Elevated WNT5A expression has been significantly correlated with increased metastatic potential of melanoma cells as well as reduced patient survival. In this thesis we investigate the possibility of impairing melanoma cell motility by targeting WNT5A signaling. Our results demonstrate that TGFβ is an unsuitable target for blocking WNT5A signaling since it mediates unpredictable effects on melanoma cell invasion. Instead, we show that the t-butyloxycarbonyl-modified WNT5A-derived hexapeptide Box5 functions a potent antagonist of WNT5A-induced signaling, migration and invasion in melanoma cells. Moreover, we demonstrate that IL-6 can drive melanoma cell motility through p38α-MAPK-dependent up-regulation of WNT5A expression and that targeting IL-6, in contrast to TGFβ, reduces melanoma cell invasion. We furthermore reveal the existence of a WNT5A-IL-6 positive feedback loop in melanoma cells that augments their invasive capacity. Concomitantly, we show that combined targeting of IL-6 and WNT5A within this loop more effectively impairs melanoma cell invasion. Taken together, our results demonstrate the possibilities of antagonizing WNT5A signaling directly (Box5) or indirectly (targeting of IL-6), which if combined can provide the basis for future therapeutic intervention of melanoma metastasis.