Cancer articles within Nature

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  • Letter |

    p53 is an important tumour suppressor gene. Two papers now show in a Kras-driven lung cancer model that p53-mediated tumour suppression is only engaged late during tumour progression, when the Kras oncogenic signal reaches a threshold sufficient to activate the ARF–p53 pathway. Therefore, p53 re-expression in p53-deficient lung tumours does not restrict early stages of tumorigenesis, but induces tumour regression of more aggressive tumours.

    • Melissa R. Junttila
    • , Anthony N. Karnezis
    •  & Carla P. Martins

  • 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

  • Letter |

    This is one of two papers showing that glioblastoma cells can differentiate into functional endothelial cells as part of the tumour vasculature. These endothelial cells are characterized by the same genetic alterations as the glioblastoma cells. The tumour-derived endothelial cells originate in putative glioblastoma-initiating cells and are functionally important for tumorigenesis.

    • Rong Wang
    • , Kalyani Chadalavada
    •  & Viviane Tabar

  • Letter |

    This is one of two papers showing that glioblastoma cells can differentiate into functional endothelial cells as part of the tumour vasculature. These endothelial cells are characterized by the same genetic alterations as the glioblastoma cells. The tumour-derived endothelial cells originate in putative glioblastoma-initiating cells and are functionally important for tumorigenesis.

    • Lucia Ricci-Vitiani
    • , Roberto Pallini
    •  & Ruggero De Maria

  • News & Views |

    Prognosis for patients with pancreatic cancer is bleak, often owing to late diagnosis. The estimate that at least 15 years pass from tumour initiation to malignancy offers hope for early detection and prevention. See Letters p.1109 & p.1114

    • E. Georg Luebeck

  • Autumn Books |

    Steve Silberman is moved by Oliver Sacks's poignant account of losing his vision through cancer.

    • Steve Silberman

  • News & Views |

    Short residence times in the bloodstream reduce the effectiveness of protein drugs. Application of an approach that combines protein and polymer engineering prolongs circulation time and increases drug uptake by tumours.

    • Jeffrey A. Hubbell

  • Letter |

    Pancreatic cancer is highly aggressive, usually because of widespread metastasis. Here, next-generation DNA sequencing has been used to detect genomic rearrangements in 13 patients with pancreatic cancer and to explore clonal relationships among metastases. The results reveal not only considerable inter-patient heterogeneity, but also ongoing genomic instability and evolution during the development of metastases.

    • Peter J. Campbell
    • , Shinichi Yachida
    •  & P. Andrew Futreal

  • Letter |

    Here, whole-genome sequencing has been used to analyse primary pancreatic tumours and one or more metastases from the same patients. The findings show that tumours are composed of several geographically distinct subclones, and allow maps to be produced showing how metastatic cancer clones evolve within the primary tumour. Moreover, a quantitative analysis of the timing of the genetic evolution of pancreatic cancer has been performed.

    • Shinichi Yachida
    • , Siân Jones
    •  & Christine A. Iacobuzio-Donahue

  • Letter |

    The aberrant expression of microRNAs and of the enzymes that control their processing has been reported in tumours, but the mechanisms involved are not clear. It is now shown that TAp63, a member of the p53 family of tumour suppressors, suppresses tumorigeneis and metastasis by directly controlling the expression of Dicer (a microRNA-processing enzyme) and Dicer-regulated microRNAs.

    • Xiaohua Su
    • , Deepavali Chakravarti
    •  & Elsa R. Flores

  • News Q&A |

    An open-source computer program flouts patents to test for cancer-causing gene mutations.

    • Alla Katsnelson

  • News & Views |

    In certain types of gastrointestinal cell, mutations in the protein KIT give rise to gastrointestinal stromal tumours. Why are other cell types that express KIT not affected? The answer lies with a second protein. See Letter p.849

    • Michael C. Heinrich
    •  & Christopher L . Corless

  • News & Views |

    Purification of the human tumour-suppressor protein BRCA2, which is crucial for DNA repair, has been a formidable challenge owing to its large size. That mission is now accomplished, providing biochemical insight. See Article p.678

    • Lee Zou

  • Letter |

    Gastrointestinal stromal tumours (GIST) are believed to arise in interstitial cells of Cajal (ICC). These authors show that the transcription factor ETV1 is required for ICC development and promotes the development of GIST. KIT, which is often activated by mutations in GIST, cooperates with ETV1 in the transformation of ICCs, in part by promoting ETV1 stabilization. Thus, a normal developmental lineage factor is switched into a tumour-promoting factor by a cooperating oncogene.

    • Ping Chi
    • , Yu Chen
    •  & Charles L. Sawyers

  • Editorial |

    An increasing number of biomedical researchers are testing their ideas on people. The early-phase clinical-trial results are a promising sign of greater cooperation between scientists and clinicians.

  • Letter |

    Progestins, used in hormone replacement therapy and contraceptives, have been suggested to promote the development of breast cancer. These authors show that the ability of progestins to induce mammary tumours in mouse models is mediated by RANKL (receptor activator of NF-KB ligand). Inhibition of RANKL could reduce tumorigenesis in hormone-induced and other mouse mammary gland tumour models, suggesting a new therapeutic approach.

    • Eva Gonzalez-Suarez
    • , Allison P. Jacob
    •  & William C. Dougall

  • Letter |

    Progestins, used in contraceptives and hormone replacement therapy, have been linked to breast cancer. These authors provide a mechanistic basis for this association. They show in a mouse model that synthetic progestins can promote mammary tumour formation by inducing RANKL (receptor activator of NF-KB ligand), which acts on mammary epithelial cells through the RANKL receptor RANK.

    • Daniel Schramek
    • , Andreas Leibbrandt
    •  & Josef M. Penninger

  • 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 |

    The ends of eukaryotic chromosomes are composed of repeat sequences known as telomeres. Various proteins bind telomeres to protect them from degradation or inappropriate DNA repair responses, and their length is maintained by a specialized reverse transcriptase, telomerase. These authors show that in the absence of telomerase, telomeres can be maintained by amplifying and recombining heterochromatin sequences there. This process requires histone methylation and two telomere-binding proteins, Pot1 and Ccq1.

    • Devanshi Jain
    • , Anna K. Hebden
    •  & Julia Promisel Cooper

  • 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

  • Letter |

    Cell cycle checkpoints, such as the S-phase checkpoint, delay cell division to give the cell time to repair any damaged DNA. Here it is shown that the MLL gene — frequently disrupted in leukaemia — is part of the S-phase checkpoint. When DNA is damaged, MLL is phosphorylated by the ATR protein, causing MLL to accumulate on chromatin and methylate histone H3 on lysine 4. This delays DNA replication. MLL translocations, such as those that occur in leukaemia, disrupt this pathway and cause genomic instability.

    • Han Liu
    • , Shugaku Takeda
    •  & James J.-D. Hsieh

  • Article |

    Adenovirus E1B-55k targets transcription factor p53 for degradation and is thought to be critical for p53 inactivation during adenovirus replication. Indeed, mutant viruses lacking E1B-55k have been tested as viral cancer therapies selective for p53-positive tumours. These authors find another adenoviral protein, E4-ORF3, to inactivate p53 independently of E1B-55k by means of a chromatin-silencing mechanism that prevents access of p53 to its DNA target sites.

    • Conrado Soria
    • , Fanny E. Estermann
    •  & Clodagh C. O’Shea

  • Letter |

    α-N-methylation is an unusual post-translational modification in which the amino-terminal residues of proteins are methylated. One example is the Ran guanine nucleotide-exchange factor, RCC1, which requires methylation for its association with chromatin. These authors describe the first α-N-methyltransferase, named N-terminal RCC1 methyltransferase (NRMT). They identify the NRMT recognition sequence and several new methylation targets, and demonstrate the importance of α-N-methylation for normal bipolar spindle formation and chromosome segregation.

    • Christine E. Schaner Tooley
    • , Janusz J. Petkowski
    •  & Ian G. Macara

  • News & Views |

    Tumour viruses can cause cancer by altering gene expression and protein activity in the host cell. Tumour adenoviruses, however, seem to go to great lengths to ensure that one particular host cell protein, p53, is suppressed.

    • Kevin M. Ryan

  • Article |

    The two hereditary breast cancer susceptibility genes, BRCA1 and BRCA2, have roles in responding to DNA damage. When they are mutated or absent, genomic instability, a contributory factor to cancer development, results. Studies of BRCA2 have been hampered by its large size, which makes purification of the full-length protein challenging. These authors report the first in vitro characterization of full-length BRCA2 and delineate the different ways by which BRCA2 facilitates RAD51-mediated homologous recombination.

    • Ryan B. Jensen
    • , Aura Carreira
    •  & Stephen C. Kowalczykowski

  • Letter |

    One model for cancer development posits that the proliferating cells in a tumour can become 'addicted' to activating mutations in an oncogene. With the realization that certain microRNAs promote tumorigenesis, it has been proposed that tumours may also become dependent on such 'oncomiRs'. Here, evidence is provided that the gene encoding microRNA-21 is an oncogene, and that in its absence, tumours undergo apoptosis and regress. Thus tumours can indeed become addicted to oncomiRs.

    • Pedro P. Medina
    • , Mona Nolde
    •  & Frank J. Slack

  • Letter |

    The ability of retrotransposons to mobilize and insert into genes presents a challenge to a cell needing to maintain its genomic integrity. These authors have studied retrotransposition in embryonic carcinoma-derived cells. On insertion into DNA, the retrotransposon is quickly silenced, but the retrotransposon-specificity of this process implies that multiple silencing mechanisms may exist. Once cells differentiate, the ability to silence newly introduced retrotransposons is lost but previously inactivated retrotransposons remain inactive.

    • Jose L. Garcia-Perez
    • , Maria Morell
    •  & John V. Moran

  • Article
    | Open Access

    These authors report and analyse the draft genome sequence of the demosponge Amphimedon queenslandica. Sponges lie on the earliest branching lineage in the animal kingdom and thus have been important in studies of the origins of multicellularity. Comparative genomic analyses presented here provide significant insights into evolutionary origins of genes and pathways related to the hallmarks of metazoan multicellularity and to cancer biology.

    • Mansi Srivastava
    • , Oleg Simakov
    •  & Daniel S. Rokhsar

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