Plasticity of melanoma in vivo: murine lesions resulting from Trp53, but not Cdk4 or Arf deregulation, display neural transdifferentiation

We previously noted that melanomas developing in <i>Cdk4</i>^{<i>R24C/R24C</i>}<i>::Tyr-NRAS</i>,<i> Arf</i>^{<i>−/−</i>}<i>::Tyr-NRAS</i> and <i>Trp53</i>^<i>F/F</i><i>::Tyr-Cre(ER)::Tyr-NRAS</i> mice exhibited differences in behaviour in vivo. We investigated this phenomenon using global gene expression profiling of lesions from the respective genotypes. While those from the <i>Cdk4-</i> and <i>Arf</i>-mutant mice exhibited similar profiles, the <i>Trp53</i>^<i>F/F</i><i>::Tyr-Cre(ER)::Tyr-NRAS</i> melanomas were strikingly different, showing relative down-regulation of melanocyte-related genes, and up-regulation of genes related to neural differentiation. Specifically, they highly expressed genes representative of the myelin-producing peripheral oligodendrite (Schwann cell) lineage, although histopathologically the lesions did not exhibit the classical features of schwannoma. As Schwann cell precursors can be a cellular origin of melanocytes, it is unsurprising that plasticity with respect to melanocyte-neural differentiation can occur in melanoma. What is surprising is the genotype proclivity. Comparison of gene expression signatures revealed that melanomas from the <i>Trp53</i>-mutant mice show significant similarities with a subset of aggressive human melanomas with relatively low levels of MITF.