Skin cancer

  • Article |

    KDM5B recruits SETDB1 to repress endogenous retroelements such as MMVL30, suppressing anti-tumour immunity, and the depletion of KDM5B induces a robust adaptive immune response and enhances the response to immune checkpoint blockade.

    • Shang-Min Zhang
    • , Wesley L. Cai
    •  & Qin Yan
  • Article |

    HLA peptidomic analysis identifies recurrent intracellular bacteria-derived peptides presented on HLA-I and HLA-II molecules in melanoma tumours, revealing how bacteria can modulate immune functions and responses to cancer therapies.

    • Shelly Kalaora
    • , Adi Nagler
    •  & Yardena Samuels
  • Article |

    Tryptophan depletion in melanoma cells after prolonged treatment with interferon-γ (IFNγ) results in ribosomal frameshifting and the production of aberrant peptides that can be presented to T cells and induce an immune response.

    • Osnat Bartok
    • , Abhijeet Pataskar
    •  & Reuven Agami
  • Article |

    A combination of clonal expansion and DNA amplification is used to sequence genetic material from individual melanocytes, shedding light on the mutational landscape of these cells and the development of melanomas.

    • Jessica Tang
    • , Eleanor Fewings
    •  & A. Hunter Shain
  • Article |

    Melanoma cells undergo less oxidative stress and less ferroptosis in lymph than in blood, owing to higher levels of oleic acid in lymph, and thus exposure to the lymphatic environment increases subsequent metastasis through blood.

    • Jessalyn M. Ubellacker
    • , Alpaslan Tasdogan
    •  & Sean J. Morrison
  • Article |

    Multiomic profiling of several cohorts of patients treated with immune checkpoint blockade highlights the presence and potential role of B cells and tertiary lymphoid structures in promoting therapy response.

    • Beth A. Helmink
    • , Sangeetha M. Reddy
    •  & Jennifer A. Wargo
  • Article |

    A mouse model of papillomavirus infection reveals that skin colonization with commensal papillomaviruses protects the immunocompetent host against chemical- and UV-induced skin cancer through CD8+ T cell immunity.

    • John D. Strickley
    • , Jonathan L. Messerschmidt
    •  & Shadmehr Demehri
  • Letter |

    A range of SF3B1 mutations promote tumorigenesis through the repression of BRD9, a core component of the non-canonical BAF complex, and correcting BRD9 mis-splicing in these SF3B1-mutant cells suppresses tumour growth.

    • Daichi Inoue
    • , Guo-Liang Chew
    •  & Robert K. Bradley
  • Letter |

    A transplantable mouse model of persistent cutaneous melanoma shows that immune-mediated tumour suppression can result in a state of melanoma–immune equilibrium, and that tissue-resident memory T cells are essential drivers of this equilibrium state.

    • Simone L. Park
    • , Anthony Buzzai
    •  & Thomas Gebhardt
  • Letter |

    The identification of an ERK2–JUNB–FRA1 signalling pathway that drives addiction to therapeutic drugs in cancer cells, and an ERK2-dependent phenotype switch that precedes cell death after drug withdrawal, may help to guide therapies that exploit the addiction phenotype.

    • Xiangjun Kong
    • , Thomas Kuilman
    •  & Daniel S. Peeper
  • Article |

    Skin stem cells, but not their progenitors, are able to form tumours owing to the ability of oncogene-targeted stem cells to increase symmetric self-renewing division and a higher p53-dependent resistance to apoptosis.

    • Adriana Sánchez-Danés
    • , Edouard Hannezo
    •  & Cédric Blanpain
  • Letter |

    Analyses of tumour samples and tumour-infiltrating lymphocytes from two patients with melanoma who were treated with adoptive T-cell therapy provide evidence for tumour escape by loss and downregulation of immunogenic antigens.

    • Els M. E. Verdegaal
    • , Noel F. C. C. de Miranda
    •  & Sjoerd H. van der Burg
  • Article |

    The protein translation rate is low in tissue stem cells and tumour-initiating cells, and genetically preventing cytosine-5 methylation on transfer RNA in skin tumours is shown to favour the maintenance of a state of translational inhibition in mice, with tumour-initiating cells in this state becoming more sensitive to cytotoxic stress.

    • Sandra Blanco
    • , Roberto Bandiera
    •  & Michaela Frye
  • Letter |

    An analysis of cancer genomic data reveals an increased rate of somatic mutations at active transcription factor binding sites located both within promoter regions and distal from genes; the increased mutation rate at these genomic regions can be explained by reduced accessibility of the protein-bound DNA to nucleotide excision repair machinery.

    • Radhakrishnan Sabarinathan
    • , Loris Mularoni
    •  & Núria López-Bigas
  • Letter |

    A known oncogene, MITF, resides in a region of chromosome 3 that is amplified in melanomas and associated with poor prognosis; now, a long non-coding RNA gene, SAMMSON, is shown to also lie in this region, to also act as a melanoma-specific survival oncogene, and to be a promising therapeutic target for anti-melanoma therapy.

    • Eleonora Leucci
    • , Roberto Vendramin
    •  & Jean-Christophe Marine
  • Article |

    Human melanoma cells grown in mice experience high levels of oxidative stress in the bloodstream such that few metastasizing cells survive to form tumours; the rare melanoma cells that successfully metastasize undergo metabolic changes that increase their capacity to withstand this stress, and antioxidant treatments increase metastasis formation by human melanoma cells, while inhibiting antioxidant pathways had the reverse effect.

    • Elena Piskounova
    • , Michalis Agathocleous
    •  & Sean J. Morrison
  • Letter |

    A novel ALK transcript expressed in a subset of human cancers, arising from a de novo alternative transcription initiation site within the ALK gene, is described; the ALK transcript encodes three protein isoforms that stimulate tumorigenesis in vivo in mouse models; resultant tumours are sensitive to treatments with ALK inhibitors, indicating a possible therapeutic avenue for patients expressing these isoforms.

    • Thomas Wiesner
    • , William Lee
    •  & Ping Chi
  • Letter |

    BRAF mutations occur frequently in melanomas, but patients generally develop resistance to agents targeting mutant BRAF; now, the persistent formation of the translation initiation complex eIF4F has been described as an indicator of multiple mechanisms of resistance that arise in BRAF-mutated tumours and as a promising therapeutic target.

    • Lise Boussemart
    • , Hélène Malka-Mahieu
    •  & Stéphan Vagner
  • Letter |

    Exposing mice with the BRAF (V600E) mutation to levels of ultraviolet radiation that mimic mild sunburn in humans is shown to induce mutations in the tumour suppressor Trp53 (TP53 in humans), accelerating the development of melanoma; these results support the use of sunscreen in individuals at risk of this cancer.

    • Amaya Viros
    • , Berta Sanchez-Laorden
    •  & Richard Marais
  • Letter |

    Patients with melanomas carrying an activating BRAF mutation respond to treatment with BRAF inhibitors although resistance to the inhibitor usually emerges; this resistance is shown to arise through increased expression of receptor tyrosine kinases such as EGFR; however, these changes decrease cell fitness and during a break from inhibitor treatment these cells are selected against, revealing that some patients who acquire EGFR expression may benefit from inhibitor re-treatment after a drug holiday.

    • Chong Sun
    • , Liqin Wang
    •  & Rene Bernards
  • Letter |

    BRAF inhibitors such as vemurafenib have shown promising effects in patients with BRAF-mutant melanomas, but the tumours generally develop resistance; vemurafenib-resistant melanomas are now shown to be drug dependent, and an intermittent dosing schedule can help prevent drug resistance.

    • Meghna Das Thakur
    • , Fernando Salangsang
    •  & Darrin D. Stuart
  • 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
  • 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
  • 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
  • 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