A major challenge for managing melanoma is its tumour heterogeneity based on individual co‐existing melanoma cell phenotypes.,These phenotypes display variable responses to standard therapies, and they drive individual steps of melanoma progression; hence, understanding their behaviour is imperative.,Melanoma phenotypes are defined by distinct transcriptional states, which relate to different melanocyte lineage development phases, ranging from a mesenchymal, neural crest‐like to a proliferative, melanocytic phenotype.,It is thought that adaptive phenotype plasticity based on transcriptional reprogramming drives melanoma progression, but at which stage individual phenotypes dominate and moreover, how they interact is poorly understood.,We monitored melanocytic and mesenchymal phenotypes throughout melanoma progression and detected transcriptional reprogramming at different stages, with a gain in mesenchymal traits in circulating melanoma cells (CTCs) and proliferative features in metastatic tumours.,Intriguingly, we found that distinct phenotype populations interact in a cooperative manner, which generates tumours of greater “fitness,” supports CTCs and expands organotropic cues in metastases.,Fibronectin, expressed in mesenchymal cells, acts as key player in cooperativity and promotes survival of melanocytic cells.,Our data reveal an important role for inter‐phenotype communications at various stages of disease progression, suggesting these communications could act as therapeutic target.
Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize.,We posit that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover metastatic melanoma biology.,Using a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, we identify melanoblast-specific genes whose expression contribute to metastatic competence and derive a 43-gene signature that predicts patient survival.,We identify a melanoblast gene, KDELR3, whose loss impairs experimental metastasis.,In contrast, KDELR1 deficiency enhances metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters.,We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation.,Our work demonstrates that the melanoblast transcriptome can be mined to uncover targetable pathways for melanoma therapy.,Metastatic cells can mimic many of the phenotypic behaviors of embryonic cells.,Here, the authors generate a melanoblast-specific transcriptome using a genetically engineered mouse model and identify KDELR3 as a pro-metastasis gene in melanoma.