Cancer archetypes co-opt and adapt the transcriptional programs of existing cellular states

Tumors evolve as independent systems comprising complex survival-ensuring functions, however the nature of these distinct processes and their recurrence across cancers is not clear. Here we propose that melanoma cancer-cells can be classified to three u0027archetypesu0027 that co-opt the neural crest, mature melanocytes, and stress gene expression programs, respectively, have a unique subclonal structure, and are conserved between zebrafish and human melanomas. Studying the natural history of a zebrafish melanoma tumor at the single-cell level, we found that one archetype exclusively exhibits the signature of the Warburg effect, suggesting that a shifting balance in energy production occurs differentially in the tumor. Deconvolving bulk human melanomas, we found that patients with a dominant fraction of the neural crest archetype show worse survival rates, indicating a clinical relevance for the composition of archetypes. Finally, we provide evidence that extending our approach to other cancer types can reveal universal and cancer-specific archetypes.