Background: At 45/105pregnancies, Malignant Melanoma (MM) is the most common cancer diagnosed in pregnant women. An aggressive course & poor outcomes are recognised to occur during pregnancy. IGF1 plays an important role in embryogenesis & cancer progression. IGF1 circulates as a complex with IGFBP4, which is cleaved by Pregnancy-Associated Plasma Protein-A (PAPP-A), resulting in release of IGF1. PAPP-A serum levels increase exponentially during pregnancy. Methods: 8 MM cell lines were cultured with pregnant & normal sera. Effect on proliferation (MTS) & invasion/migration (wound healing & matrigel transwell assays) were analysed. PAPP-A expression in human MM & cell lines was analysed by PCR, ELISA & IHC. Transient siRNA knock-down of PAPP-A & downstream gene/protein expression were confirmed. Functional assays were performed after PAPP-A knockdown at 24, 48 & 72hrs. An avian neural crest cell migration assay was used to confirm effects in-vivo. Furthermore, effect of PAPP-A neutralising Ab on cell motility & migration induced by sera was analysed. Results: PAPP-A is widely expressed in MM tumors and cell lines. While the proliferation of MM cells did not change with PAPP-A knockdown, migratory & invasive capacity was significantly decreased (>40% p<0.05). This effect was confirmed in-vivo. The neutralizing Ab attenuated invasion and migration of MM cells, confirming the knockdown results. PAPP-A levels in pregnant sera were 70-fold higher than in control sera. Treatment of MM cells with this serum led to decreased proliferation, but enhanced migration & invasion of MM cells in-vitro. Using an antibody against PAPP-A to evaluate its role in this, we detected a reversion of pregnant serum-induced invasion and migration. Conclusions: Pregnant sera enhances the migratory & invasive behaviour of MM cells in-vitro, which can be effectively attenuated by Ab against PAPP-A. Reduced invasion & migration after PAPP-A knockdown suggests a potential therapeutic target in treatment of MM. This study also gives an indication towards a biological mechanism (PAPP-A) involved in MM progression during pregnancy.