LADON, a Natural Antisense Transcript of NODAL, Promotes an Invasive Behaviour in Melanoma Cells

The TGFβ family member NODAL, known for its role during embryonic development, has also been associated with tumor progression in several cancers. Some of the evidence supporting its involvement in melanoma appeared contradictory, suggesting that NODAL in this context might rely on a non-canonical signalling mode. We found that NODAL inactivation in a metastatic melanoma cell line prevents the cells from acquiring invasive behaviour. However, we show that this phenotype does not result from the absence of NODAL, but from a defect in the expression of a natural antisense transcript of NODAL, here called LADON. We found that LADON promotes the mesenchymal to amoeboid transition that is critical to melanoma cell invasiveness, and that a WNT/β-CATENIN signalling-dependent increase in LADON expression is required to complete this transition. LADON’s downstream effectors include, among others, the proto-oncogene MYCN. These results identify LADON as a player in the regulatory network that governs tumor progression in melanoma, and possibly in other types of cancer.