LADON, a natural antisense transcript of NODAL, promotes metastasis in melanoma by repressing NDRG1

The TGFβ family member NODAL, primarily known for its role during embryonic development, has also been associated with tumor progression in a number of cancers. Some of the evidence supporting its involvement in melanoma has appeared contradictory, suggesting that NODAL in this context might rely on a non-canonical mode of signaling. To investigate this possibility we studied how a deletion of NODAL affected cell behavior in a metastatic melanoma cell line. The mutation does prevent melanoma cells from acquiring an invasive behavior. However, this phenotype was found to result not from the absence of NODAL, but from the disabled expression of a natural antisense transcript of NODAL now called LADON. Its expression promotes the mesenchymal to amoeboid transition that is critical to melanoma cells9 invasiveness. Our analyses revealed that the increase in LADON expression necessary to complete this transition is dependent on WNT/β-CATENIN signaling and that its downstream effectors include MYCN and the metastasis suppressor NDRG1, which controls changes in the cytoskeleton. These results identify LADON as a player in the network of interactions governing tumor progression in melanoma, and suggest a similar implication in other cancer types.