title: Plasticity of melanoma in vivo: murine lesions resulting from Trp53, but not Cdk4 or Arf deregulation, display neural transdifferentiation.
abstract: We previously noted that melanomas developing in Cdk4(R24C/R24C) ::Tyr-NRAS, Arf(-/-) ::Tyr-NRAS and Trp53(F/F) ::Tyr-Cre(ER)::Tyr-NRAS 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 Cdk4- and Arf-mutant mice exhibited similar profiles, the Trp53(F/F) ::Tyr-Cre(ER)::Tyr-NRAS 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 Trp53-mutant mice show significant similarities with a subset of aggressive human melanomas with relatively low levels of MITF.
authors.affiliation: Queensland Institute of Medical Research, Herston, Qld, Australia.
authors.forename: Herlina Y
authors.initials: HY
authors.lastname: Handoko
authors.forename: Glen M
authors.initials: GM
authors.lastname: Boyle
authors.forename: Blake
authors.initials: B
authors.lastname: Ferguson
authors.forename: H Konrad
authors.initials: HK
authors.lastname: Muller
authors.forename: H Peter
authors.initials: HP
authors.lastname: Soyer
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Walker
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D054338:Cell Transdifferentiation / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D059748:Proteolysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; D051358:Cyclin-Dependent Kinase 4
keywords: Trp53; melanoma; mice; transdifferentiation