Featured
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Research Highlights |
Cancer detection: Tracking roving cancer cells
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News & Views |
Drug-tolerant insurgents
Some cancer cells that become tolerant to a drug remain resistant even after its withdrawal, yet these cells eventually become sensitive to the drug again. The underlying molecular mechanism is unusual.
- Paul Workman
- & Jon Travers
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Research Highlights |
Cancer biology: Cellular battering ram
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Opinion |
Point: Hypotheses first
There is little to show for all the time and money invested in genomic studies of cancer, says Robert Weinberg — and the approach is undermining tried-and-tested ways of doing, and of building, science. This Opinion piece is part of a linked pair; see also Counterpoint: Data First by Todd Golub.
- Robert Weinberg
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Opinion |
Counterpoint: Data first
Large, unbiased genomic surveys are taking cancer therapeutics in directions that could never have been predicted by traditional molecular biology, says Todd Golub. This Opinion piece is part of a linked pair; see also Point: Hypothesis First by Robert Weinberg.
- Todd Golub
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News |
Breast cancer gene patents judged invalid
Court ruling may spell bad news for biotech industry.
- Meredith Wadman
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Letter |
Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis
Cancer 'chemoprevention' uses substances to reverse, suppress or prevent the initial phase of carcinogenesis or the progression of neoplastic cells to cancer cells. Here it is shown that treatment with TRAIL proteins and all-trans-retinyl acetate can cause the death, in vitro and in vivo, of premalignant cells deficient in the adenomatous polyposis coli gene. Normal cells are unaffected. Selectively eliminating premalignant tumour cells in this way is thus an effective method for chemoprevention.
- Ling Zhang
- , Xiaoyang Ren
- & Xiangwei Wu
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News |
Cancer genes silenced in humans
Tiny particles carrying short strands of RNA can interfere with protein production in tumours.
- Janet Fang
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Article |
Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia
A new mouse model is developed in which haematopoietic malignancies are caused by genetic changes in the microenvironment of blood cells. Deletion in bone progenitor cells of Dicer1, a gene involved in microRNA processing, leads to a myelodysplastic syndrome-like phenotype which can progress to leukaemia. Deregulation of Sbds, which is mutated in human Schwachman–Bodian–Diamond syndrome, may be involved in this process.
- Marc H. G. P. Raaijmakers
- , Siddhartha Mukherjee
- & David. T. Scadden
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Article |
Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence
Cellular senescence — an irreversible cell-cycle arrest — has been implicated in suppressing tumour formation or growth. A new cellular signalling pathway that drives senescence has now been identified. This pathway does not involve most known mediators of senescence, and instead signals via the proteins Atf4, p27 and p21. Inactivating the proto-oncogene Skp2 in the context of oncogenic signalling can induce senescence through this new pathway, indicating that drugs that target Skp2 might be useful in cancer treatment.
- Hui-Kuan Lin
- , Zhenbang Chen
- & Pier Paolo Pandolfi
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News & Views |
A lower bar for senescence
Cellular senescence is a physiological mechanism for thwarting the proliferation of tumour cells. Encouraging cancer-prone cells to senesce might therefore be a way to nip this disease in the bud.
- Manuel Serrano
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News & Views |
Inhibitors that activate
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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Letter |
B-cell-derived lymphotoxin promotes castration-resistant prostate cancer
In a mouse model of prostate cancer it is shown that infiltrating B cells promote tumorigenesis by secreting lymphotoxin. Lymphotoxin accelerates the emergence of castration-resistant prostate tumours in this model. Interfering with this pathway may offer therapeutic strategies for androgen-independent prostate cancer.
- Massimo Ammirante
- , Jun-Li Luo
- & Michael Karin
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Research Highlights |
Cancer genomics: Melanoma's mutations
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Research Highlights |
Cancer biology: Arsenic activation
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News |
Blame it on the B cells
Immune cells seem to spark recurrent prostate cancer in mice.
- Brian Vastag
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Letter |
Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses
In response to oncogenic stress, the tumour suppressor ARF activates the p53 protein. ARF protein is highly stable in most human cell lines, so it has been thought that ARF activation occurs mainly at the level of transcription. Here, however, ARF is shown to be unstable in normal human cells but stable in cancer cells, through a transcription-independent mechanism. A ubiquitin ligase for ARF is identified and shown to promote ARF degradation in normal cells. This activity is prevented in cancer cells, stabilizing ARF.
- Delin Chen
- , Jing Shan
- & Wei Gu
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Letter |
Heteroplasmic mitochondrial DNA mutations in normal and tumour cells
Each human cell contains hundreds of copies of mitochondrial DNA (mtDNA), making it difficult to characterize mtDNA completely. Here, massively parallel sequencing-by-synthesis of mtDNA reveals widespread heterogeneity (heteroplasmy) in the mtDNA of normal human cells, and homoplasmic and heteroplasmic mutations in cancer cells. The findings provide new insight into the nature and variability of mtDNA sequences, with implications for forensic analysis and the development of biomarkers for cancer.
- Yiping He
- , Jian Wu
- & Nickolas Papadopoulos
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Research Highlights |
Molecular imaging: Tumour glows out
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Letter |
RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
The RAS–RAF signalling pathway is an attractive target for drug development in oncology, and several RAF inhibitors are being tested in clinical trials. Here and in an accompanying paper, RAF inhibitors are shown to have opposing roles, functioning as either inhibitors or activators of RAF depending on the cellular context and mutational status of RAF. The mechanistic basis for these opposing roles is dissected. The results have implications for the clinical use of these inhibitors and for the design of kinase inhibitors.
- Poulikos I. Poulikakos
- , Chao Zhang
- & Neal Rosen
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Letter |
Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal
Genomic instability has been implicated in tumour development. Here, a new mouse model of Kras-driven lung tumours has been developed, in which genomic instability is caused by overexpression of the mitotic checkpoint protein Mad2. In this model, inhibiting Kras leads to tumour regression, as shown previously. But tumours recur at a much higher rate.
- Rocio Sotillo
- , Juan-Manuel Schvartzman
- & Robert Benezra
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News |
Personalized biomarkers monitor cancer
Pilot study harnesses sequencing power to track tumours.
- Heidi Ledford
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Article |
The landscape of somatic copy-number alteration across human cancers
One way of discovering genes with key roles in cancer development is to identify genomic regions that are frequently altered in human cancers. Here, high-resolution analyses of somatic copy-number alterations (SCNAs) in numerous cancer specimens provide an overview of regions of focal SCNA that are altered at significant frequency across several cancer types. An oncogenic function is also found for the anti-apoptosis genes MCL1 and BCL2L1, which reside in amplified genome regions in many cancers.
- Rameen Beroukhim
- , Craig H. Mermel
- & Matthew Meyerson
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News |
How accurate are cancer cell lines?
Some argue that tumour cells obtained directly from patients are the best way to study cancer genomics.
- Brendan Borrell
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Brief Communications Arising |
Chronic DLL4 blockade induces vascular neoplasms
- Minhong Yan
- , Christopher A. Callahan
- & Greg D. Plowman
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Research Highlights |
Stem cells: Uneven divide
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Letter |
TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia
Chronic myeloid leukaemia is caused by a BCR-ABL fusion, a constitutively active tyrosine kinase that, it is believed, leads to suppression of the forkhead O transcription factors (FOXO). Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Foxo3a is now shown to have an essential role in the maintenance of CML LICs in a mouse model.
- Kazuhito Naka
- , Takayuki Hoshii
- & Atsushi Hirao
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Books & Arts |
The woman behind HeLa
Steve Silberman enjoys a moving account that probes racial and ethical issues in medicine through the story of the young mother whose death from cancer led to the first immortal cell line.
- Steve Silberman
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News & Views |
Big roles for small RNAs
Embryonic stem cells can create copies of themselves, but can also mature into almost any type of cell in the body. Tiny gene regulators called microRNAs are now shown to have a role in directing these properties.
- Frank J. Slack
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Letter |
RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth
The RAS–RAF signalling pathway is an attractive target for drug development in oncology, and several RAF inhibitors are being tested in clinical trials. Here and in an accompanying paper, RAF inhibitors are shown to have opposing roles, functioning as either inhibitors or activators of RAF depending on the cellular context and mutational status of RAF. The mechanistic basis for these opposing roles is dissected. The results have implications for the clinical use of these inhibitors and for the design of kinase inhibitors.
- Georgia Hatzivassiliou
- , Kyung Song
- & Shiva Malek
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News |
Project set to map marks on genome
Consortium sets sights on the differences that make us different.
- Alison Abbott
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Research Highlights |
Cancer biology: Weighted cancer risk
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News Feature |
Translational research: Talking up translation
Alan Ashworth took a cancer drug from Petri dish to patients in near record speed. Daniel Cressey meets a biologist who is evangelical about translational research.
- Daniel Cressey
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Letter |
Hsp70 stabilizes lysosomes and reverts Niemann–Pick disease-associated lysosomal pathology
Heat shock protein 70 (Hsp70) is a molecular chaperone which, by inhibiting lysosomal membrane permeabilization, promotes the survival of stressed cells. Hsp70 is now shown to stabilize lysosomes by binding to an anionic phospholipid, BMP, resulting in stimulation of acid sphingomyelinase (ASM) activity. Notably, the decreased ASM activity and lysosomal stability seen in patients with Niemann–Pick disease can be corrected by treatment with recombinant Hsp70.
- Thomas Kirkegaard
- , Anke G. Roth
- & Marja Jäättelä
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News |
Lawsuit rekindles gene-patent debate
Criticism of exclusive licences puts university policies in the spotlight.
- Brendan Borrell
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News |
Genomics boosts brain-cancer work
Molecular findings start to open up avenues of diagnosis and treatment.
- Erika Check Hayden
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Research Highlights |
Cancer biology: Kicking out cancer cells
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Letter |
Interaction between RasV12 and scribbled clones induces tumour growth and invasion
In human tumours, complex cell interactions in the tumour and its microenvironment are thought to have an important role in tumorigenesis and cancer progression. In a genetically well-defined model system in Drosophila, clones of cells bearing different mutations are now shown to cooperate to promote tumour growth and invasion. This interaction involves JNK signalling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines.
- Ming Wu
- , José Carlos Pastor-Pareja
- & Tian Xu
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Letter |
Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma
The role of B-cell-receptor (BCR) signalling in human B cell lymphomas has been a long-standing question, with genetic and functional evidence for its oncogenic role in human lymphomas lacking. Here, a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like subtype of diffuse large B-cell lymphoma is described and analysed, with potential implications for future therapeutic strategies.
- R. Eric Davis
- , Vu N. Ngo
- & Louis M. Staudt
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Letter |
Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes
Clear cell renal carcinoma, the most common form of adult kidney cancer, is often characterized by the presence of inactivating mutations in the VHL gene. A large survey for somatic mutations now identifies inactivating mutations in two genes encoding enzymes involved in histone modification, highlighting the role of mutations in components of the chromatin modification machinery in human cancer.
- Gillian L. Dalgliesh
- , Kyle Furge
- & P. Andrew Futreal
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