This study explores how RNA-binding proteins (RBPs) influence melanoma development and metastasis. The researchers combined RNA interactome capture (RIC), gene silencing, and functional assays to study the RNA-binding profiles of non-tumoral and metastatic melanoma. They mapped 477 RBPs, many which did not have classical RNA-binding domains. They found that metastatic cells exhibit major changes in their RNA-binding activity, suggesting that there is a reprogramming of post-transcriptional control. PDIA6 was identified as a RBP that had an unexpected RNA-binding function. Without it, metastatic melanoma was unable to survive. The researchers found that PDIA6’s RNA-binding ability and not its enzymatic activity was crucial in promoting tumor growth.