Skin cancer articles within Nature

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  • Letter |

    Individuals with the red hair/fair skin phenotype usually carry a polymorphism in the gene encoding the melanocortin 1 receptor (Mc1r) that results in the production of pigment containing a high pheomelanin-to-eumelanin ratio; here it is shown in a mouse model that inactivation of Mc1r promotes melanoma formation in the presence of the Braf oncogene, thus suggesting that pheomelanin synthesis is carcinogenic by an ultraviolet-radiation-independent mechanism.

    • Devarati Mitra
    • , Xi Luo
    •  & David E. Fisher

  • News & Views |

    Tumour cells can respond to targeted immune-cell therapies by losing proteins that mark them as being cancerous. Subverting this resistance mechanism may lead to more durable cancer-treatment strategies. See Letter p.412

    • Antoni Ribas
    •  & Paul C. Tumeh

  • Letter |

    A genetically engineered mouse model is used to determine the mechanism of acquired resistance to adoptive therapy with cytotoxic T cells specific for a melanocytic differentiation antigen; tumour necrosis factor (TNF)-α is identified as a crucial factor that causes reversible dedifferentiation of mouse and human melanoma cells.

    • Jennifer Landsberg
    • , Judith Kohlmeyer
    •  & Thomas Tüting

  • Letter
    | Open Access

    Whole-genome sequencing of 25 metastatic melanomas and matched germline DNA in humans reveals that the highest mutation load is associated with chronic sun exposure, and that the PREX2 gene is mutated in approximately 14 per cent of cases

    • Michael F. Berger
    • , Eran Hodis
    •  & Levi A. Garraway

  • News & Views |

    A drug for treating melanoma is ineffective in colorectal cancers that have the same causative mutation. Studies of how cells adapt to the drug reveal why this is so, and suggest combination therapies that may be more effective. See Letter p.100

    • David B. Solit
    •  & Pasi A. Jänne

  • News & Views |

    The efficacy of the anticancer drug vemurafenib, which is used to treat metastatic melanoma, is plagued by acquired resistance. A picture of how such resistance develops is emerging. See Letter p.387

    • Hugo Lavoie
    •  & Marc Therrien

  • News & Views |

    Skin-cancer stem cells secrete a factor that organizes a blood-supply system to fuel tumour growth. But the same factor has another sinister function — it stimulates the stem cells to propagate uncontrollably. See Letter p.399

    • Salvador Aznar Benitah

  • Letter |

    In a zebrafish model of melanoma driven by activated BRAF, this study finds expression of a gene signature indicative of disrupted terminal differentiation of neural crest progenitors. A chemical screen led to the identification of leflunomide as an inhibitor of neural crest stem cells. Leflunomide inhibits dihydroorotate dehydrogenase and thereby transcriptional elongation, including genes involved in neural crest development and melanoma growth. Leflunomide has anti-melanoma activity in the zebrafish model and human melanoma xenografts, and might prove useful as an anticancer drug.

    • Richard Mark White
    • , Jennifer Cech
    •  & Leonard I. Zon

  • Letter |

    Using a zebrafish model of melanoma, this study has searched for genes that can cooperate with mutated BRAF, a frequent oncogenic event in human melanomas. It is found that SETDB1 can accelerate melanoma formation in fish and resides in a region frequently amplified in human melanomas. SETDB1, a histone methylating enzyme, is also frequently overexpressed in human melanomas and functions at least in part by regulating the expression of HOX genes.

    • Craig J. Ceol
    • , Yariv Houvras
    •  & Leonard I. Zon

  • Letter |

    The histone variant mH2A is shown to be expressed at reduced levels in many melanomas. Loss of mH2A promotes tumour growth and metastasis via transcriptional upregulation of CDK8, a known oncogene. This study therefore reveals a new tumour suppression mechanism exerted by epigenetic modifications.

    • Avnish Kapoor
    • , Matthew S. Goldberg
    •  & Emily Bernstein

  • News & Views |

    The promise of an exciting new drug that inhibits the mutant B-RAF protein in skin cancer is marred by the fact that most patients relapse within a year. Fresh data hint at how such resistance emerges. See Letters p.968 & p.973

    • David Solit
    •  & Charles L. Sawyers

  • News |

    Learning how melanoma fights back may yield new therapies.

    • Heidi Ledford

  • Letter |

    Recent data from early clinical trials in melanoma patients carrying mutations in the B-RAF gene have shown promising results with the B-RAF kinase inhibitor PLX4032; however, many patients eventually develop resistance to this treatment. Two papers now uncover possible mechanisms of resistance to PLX4032. One paper shows that upregulation of MAP3K8 (which encodes COT) can confer resistance of melanoma cells to B-RAF inhibitors, whereas another paper found that melanomas can acquire resistance due to mutations of N-RAS or increased expression of PDGFRβ. Each of these resistance mechanisms seems to apply to at least some patients on recent PLX4032 trial, whereas, surprisingly, so far no secondary B-RAF mutations have been observed.

    • Cory M. Johannessen
    • , Jesse S. Boehm
    •  & Levi A. Garraway

  • Letter |

    Recent data from early clinical trials in melanoma patients carrying mutations in the B-RAF gene have shown promising results with the B-RAF kinase inhibitor PLX4032; however, many patients eventually develop resistance to this treatment. Two papers now uncover possible mechanisms of resistance to PLX4032. One paper shows that upregulation of MAP3K8 (which encodes COT) can confer resistance of melanoma cells to B-RAF inhibitors, whereas another paper found that melanomas can acquire resistance due to mutations of N-RAS or increased expression of PDGFRβ. Each of these resistance mechanisms seems to apply to at least some patients on recent PLX4032 trial, whereas, surprisingly, so far no secondary B-RAF mutations have been observed.

    • Ramin Nazarian
    • , Hubing Shi
    •  & Roger S. Lo

  • Article |

    A new approach is used to target BET family bromodomains which are found in transcriptional regulators where they mediate the recognition of acetyl-lysine chromatin marks. Structural data reveal how the compound JQ1 binds to the bromodomain of BRD4. BRD4 has been implicated in a subtype of human squamous carcinomas, and JQ1 is found to inhibit the growth of BRD4 dependent tumours in mouse models.

    • Panagis Filippakopoulos
    • , Jun Qi
    •  & James E. Bradner

  • Letter |

    PLX4032 is a selective inhibitor of the B-RAF protein that has shown promising results in an early clinical trial in melanoma patients with an activating mutation in B-RAF. Now the structure and function of this inhibitor are described. Translational data from a phase I trial show that clinical efficacy requires a substantial degree of inhibition of the ERK pathway downstream of B-RAF. The data also show that BRAF-mutant melanomas are highly dependent on B-RAF activity.

    • Gideon Bollag
    • , Peter Hirth
    •  & Keith Nolop

  • News & Views |

    Tumour cells are non-uniform. The question is whether a distinct subpopulation of the cells drives tumour growth and generates cellular variation. To answer this, the data must be interpreted carefully.

    • Peter Dirks

  • Article |

    Ultraviolet radiation causes damage to DNA in skin cells, blocking DNA replication and causing mutations that can lead to cancer. One way in which the cell deals with such damage involves specialized DNA polymerases, such as Polη, that can bypass lesions. Here the crystal structure is presented of Pol? in complex with a thymine–thymine dimer and with undamaged DNA. The bulky thymine dimer is accommodated in an atypically large active site, and stabilized by interactions not found in other polymerases.

    • Timothy D. Silverstein
    • , Robert E. Johnson
    •  & Aneel K. Aggarwal

  • Article |

    When oxygen levels drop in a tissue, the transcription factor hypoxia-inducible factor (HIF) is activated to regulate the cellular response. HIFα levels are increased in most solid tumours and this correlates with a poor prognosis, for unknown reasons. Here it is shown that HIF-1, the worm version of HIFα, protects germ cells from DNA-damage-induced death. It does this remotely, by increasing the production of the TYR-2 protein in distant neurons. Inhibiting a human TYR-2 homologue promotes apoptosis in melanoma cells.

    • Ataman Sendoel
    • , Ines Kohler
    •  & Michael O. Hengartner

  • Letter |

    Calcineurin inhibitors are the mainstay of immunosuppressive treatment for organ transplant recipients. However, treatment with these drugs commonly leads to squamous cell carcinoma (SCC) of the skin. It is shown here that an intact calcineurin/NFAT signalling pathway is important for suppressing SCC development. Inhibition of this pathway leads to increased expression of the ATF3 protein, which has a key role in tumorigenesis.

    • Xunwei Wu
    • , Bach-Cuc Nguyen
    •  & G. Paolo Dotto

  • News |

    Tiny particles carrying short strands of RNA can interfere with protein production in tumours.

    • Janet Fang

  • News & Views |

    Inhibitors of RAF enzymes can suppress or activate the same signalling pathway. The details of how this happens provide a cautionary note for those targeting the pathway for anticancer drug discovery.

    • Karen Cichowski
    •  & Pasi A. Jänne

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