Featured
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Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis
The ras family of oncogenes consists of H-ras, K-ras and N-ras, and usually only one of these genes is mutated in a given tumour type. In this study, K-ras is found to promote the activation of wild-type H-ras and N-ras in a manner dependent on the Ras guanine nucleotide exchange factor Son of sevenless.
- Hao-Hsuan Jeng
- , Laura J Taylor
- & Dafna Bar-Sagi
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A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis
Interactions of cells with extracellular matrix are important in normal physiology and cancer metastasis. Here, an extracellular matrix molecule array is developed and used to show that conserved changes in adhesive properties are associated with metastasis, including binding to fibronectin in combination with galectin-3, galectin-8 or laminin.
- Nathan E. Reticker-Flynn
- , David F. Braga Malta
- & Sangeeta N. Bhatia
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Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres
Single-walled carbon nanotubes can selectively stabilize telomeric i-motif DNA and have been suggested as a treatment for cancer. Here, carbon nanotubes are found to inhibit telomerase activity by stabilizing i-motif DNA, leading to telomere uncapping and altered telomere function in cancer cells.
- Yong Chen
- , Konggang Qu
- & Xiaogang Qu
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| Open AccessEnhanced HSP70 lysine methylation promotes proliferation of cancer cells through activation of Aurora kinase B
HSP70 is a molecular chaperone that aids protein folding. In this study, HSP70 is shown to be methylated and this post-translationally modified protein is elevated in expression in human cancers and promotes the activity of Aurora kinase B.
- Hyun-Soo Cho
- , Tadahiro Shimazu
- & Ryuji Hamamoto
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TGFβ induces the formation of tumour-initiating cells in claudinlow breast cancer
TGF-β signalling suppresses tumorigenesis in breast cancer cells but its effects on breast cancer initiating cells have not been reported. Using cells in culture, Brunaet al. show that TGF-β increases breast cancer initiating cell numbers in cells that have low levels of the tight junction protein claudin.
- Alejandra Bruna
- , Wendy Greenwood
- & Carlos Caldas
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| Open AccessHigh-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring
Environmental factors can influence one's susceptibility to cancer, but it is not clear whether such an influence extends beyond the directly exposed generations. Here, feeding pregnant rats with a high-fat diet or a hormone derivative, the authors observe increased breast cancer risk in up to three subsequent generations.
- Sonia de Assis
- , Anni Warri
- & Leena Hilakivi-Clarke
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Lysine methylation of VCP by a member of a novel human protein methyltransferase family
Methyltransferases modify cellular proteins in addition to DNA and histones. These authors identify a new family of lysine-specific methyltransferases and show that a member of this family, which is associated with tumour metastasis, methylates the ATP-dependent protein chaperone VCP/p97.
- Stefan Kernstock
- , Erna Davydova
- & Pål Ø. Falnes
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DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes
Cancer cells form by somatic mutations and natural selection, but how these factors affect tumorigenesis is not clear. Here, somatic mutations are characterized in human cancer genomes, revealing that DNA replication timing influences the frequency of single-nucleotide variants in different genomic regions.
- Yong H Woo
- & Wen-Hsiung Li
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FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage
The protein ataxia-telangiectasia mutated (ATM) detects DNA damage and can trigger cellular apoptosis, but how this process is regulated at the molecular level is unclear. Here, Chunget al. show that the transcription factor FOXO3 controls the formation of ATM-containing signalling complexes at sites of DNA damage that trigger apoptosis.
- Young Min Chung
- , See-Hyoung Park
- & Mickey C.-T. Hu
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Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis
Fas-associated protein with death domain (FADD) is part of a signalling complex that controls some forms of programmed cell death. Lee and colleagues demonstrate that FADD ubiquitination by the E3 ubiquitin ligase MKRN1 regulates FADD protein stability and thereby cell death.
- Eun-Woo Lee
- , Jung-Hoon Kim
- & Jaewhan Song
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Tumour lineage-homing cell-penetrating peptides as anticancer molecular delivery systems
Cell-penetrating peptides can be used to deliver nucleic acids and proteins to cells, however they lack selectivity. In this study, cell-penetrating peptides are generated that can selectively target tumour cells of different cellular origins and these may be useful in the treatment of cancer.
- Eisaku Kondo
- , Ken Saito
- & Masayuki Matsushita
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| Open AccessProtein L-isoaspartyl methyltransferase regulates p53 activity
Protein L-isoaspartyl methyltransferase (PIMT) is a carboxyl methyltransferase, but its role in regulating the tumour suppressor p53 is unclear. Here, PIMT is shown to methylate p53, obstructing the tumour suppressor function of p53 through reduced protein levels and stability.
- Jae-Cheol Lee
- , Sung-Ung Kang
- & Jeung-Whan Han
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SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane
PTEN is a tumour suppressor that inhibits activation of the phosphatidylinositol 3-kinase pathway. These authors show that PTEN is SUMOylated on two lysine residues and that this modification is required for binding to acidic phospholipids and blocking tumour formation in mice.
- Jian Huang
- , Jie Yan
- & Jianxiu Yu
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Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell
CD44 is a cell surface protein that is a marker for stem cell-like cancer cells and has a role in invasion and metastasis. Here, epithelial splicing regulatory protein 1 is shown to generate a CD44 variant protein that enhances metastasis in a mouse model and protects cells from oxidative stress.
- Toshifumi Yae
- , Kenji Tsuchihashi
- & Osamu Nagano
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| Open AccessMelanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment
Exposure to ultraviolet light is responsible for a large proportion of melanomas but the molecular mechanisms are unknown. In this study, melanoma is found to be induced in mice by UVA and UVB light in a pigment-dependent and -independent manner, respectively, resulting in different types of DNA damage.
- Frances P. Noonan
- , M. Raza Zaidi
- & Edward C. De Fabo
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Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC
Metformin is used to treat diabetes and its use has been associated with reduced cancer incidence, but the mechanism is unclear. In this study, metformin is shown to alter microRNA expression including an increase in mir-33a, which decreases the expression of the oncogenec-Myc.
- Giovanni Blandino
- , Mariacristina Valerio
- & Sabrina Strano
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A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response
The bone morphogenetic protein (BMP) and Smad1 signalling pathway is required for embryogenesis. In this study, Smad1 is shown to be phosphorylated by Atm in response to DNA damage and this results in elevated Smad1 signalling, thus uncovering a new role for this pathway in the DNA damage response.
- Jenny Fung Ling Chau
- , Deyong Jia
- & Baojie Li
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Polyploid cells rewire DNA damage response networks to overcome replication stress-induced barriers for tumour progression
Tumour cells are subject to replication stress but how cells overcome damage without inducing senescence and apoptotic pathways is unclear. Here, the authors study polyploidy in cancer cells and show that this blocks apoptotic and senescent pathways, resulting in the induction of proteins involved in DNA repair.
- Li Zheng
- , Huifang Dai
- & Binghui Shen
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Reliable detection of subclonal single-nucleotide variants in tumour cell populations
The detection of subclonal variants in heterogeneous cancer specimens is a challenge due to errors that occur during sequencing. In this study, a statistical algorithm and a sequencing strategy are reported that circumvent this issue and can accurately detect variants at a frequency as low as 1/10,000.
- Moritz Gerstung
- , Christian Beisel
- & Niko Beerenwinkel
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| Open AccessCancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels
Radiotherapy is used to treat many cancers but radiation-resistant cells can result in recurrence of the tumour. Here, Harada and colleagues develop a method to track cells that persist after radiation treatment and show that the cells acquire transcriptional activity of HIF-1 and move towards blood vessels.
- Hiroshi Harada
- , Masahiro Inoue
- & Masahiro Hiraoka
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Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance
B-RAF is mutated in a large proportion of melanomas, and the first small molecule inhibitor has recently been approved for melanoma treatment. Here, by exome sequencing melanoma samples, Shi and colleagues show that B-RAF is amplified in tumours that have acquired resistance to the B-RAF inhibitor vemurafenib.
- Hubing Shi
- , Gatien Moriceau
- & Roger S. Lo
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| Open AccessAn intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid
β-Catenin can be oncogenic but finding inhibitors has been a challenge. Here, five compounds are identified, which attenuate transcriptional β-catenin outputs in colorectal cancer cells, and the response to one of them is shown to require an intrinsically labile α-helix next to the BCL9-binding site in β-catenin.
- Marc de la Roche
- , Trevor J. Rutherford
- & Mariann Bienz
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miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia
HOX9AandMEIS1are key oncogenes in MLL-rearranged leukaemia. miRNA-196b is shown here to directly suppress their expression and delay MLL-fusion-mediated leukaemia, but to also cause an aggressive leukaemia phenotype when expressed ectopically, suggesting that it targets tumour suppressors as well.
- Zejuan Li
- , Hao Huang
- & Jianjun Chen
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EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex
The role of ephrin receptors in tumour development and progression has remained controversial. Liet al. show that kinase activation of ephrin-B3 inhibits non-small-cell lung cancer migration both in vitro and in vivo, which depends on a novel interacting partner, RACK 1, in a ternary complex with PP2A and Akt.
- Guo Li
- , Xiao-Dan Ji
- & Dong Xie
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Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease
The histone methyltransferase Ezh2 is thought to have a dual function both as a tumour suppressor and an oncogene. Using mouse models with Ezh2 gain-of-function, Herrera-Merchanet al. show that Ezh2 expression in HSCs severely compromises hematopoietic function, leading to myeloproliferative disease.
- A. Herrera-Merchan
- , L. Arranz
- & S. Gonzalez
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Programmable multivalent display of receptor ligands using peptide nucleic acid nanoscaffolds
Multivalent display of integrin antagonists enhances their efficacy, but current synthetic scaffolds used to display ligands are limited in range and precision. Englundet al. develop a new scaffold to study the multivalent effects of integrin antagonists across wide ranges of ligand number, density, and 3D arrangement.
- Ethan A. Englund
- , Deyun Wang
- & Daniel H. Appella
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A role for T-bet-mediated tumour immune surveillance in anti-IL-17A treatment of lung cancer
The tumour microenvironment is often found to be immunosuppressive. Reppert and colleagues show that human and murine lung tumours harbour IL-17A-producing T cells, and that blocking IL-17A increases survival in mice, suggesting that anti-IL-17A therapy may be useful in treating lung cancer.
- S. Reppert
- , I. Boross
- & S. Finotto
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| Open AccessActivin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response
Activin is known to have a role in wound healing, but its role in skin cancer is unknown. Antsiferovaet al. show that activin is elevated in human skin tumours, and by modulating epidermal immune cells, exacerbates tumour progression in a mouse model of skin cancer.
- Maria Antsiferova
- , Marcel Huber
- & Sabine Werner
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P-Rex1 is required for efficient melanoblast migration and melanoma metastasis
The processes that regulate melanoblast migration during development are also thought to be involved in melanoma metastasis. Here, Prex1 null mice are shown to have a melanoblast migration defect and, when crossed to a mouse model of melanoma, are resistant to metastasis, suggesting a role for Prex1 in metastatic melanoma.
- Colin R. Lindsay
- , Samuel Lawn
- & Owen J. Sansom
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| Open AccessGenome-wide functional screening of miR-23b as a pleiotropic modulator suppressing cancer metastasis
microRNAs are known to be deregulated in cancer. Using a screen for microRNAs that alter cell migration, Zhanget al. show that mir-23b blocks cell migration in vitro and in vivoand is reduced in expression in human colon cancer, suggesting a therapeutic potential for this microRNA.
- Hanshuo Zhang
- , Yang Hao
- & Jianzhong Jeff Xi
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| Open AccessSelective inhibition of microRNA accessibility by RBM38 is required for p53 activity
MicroRNAs bind to the 3′-untranslated region of genes to regulate expression. In this study, an RNA-binding protein, RMB38, is shown to selectively regulate the access of some microRNAs to their targets, and control the expression of some p53 target genes.
- Nicolas Léveillé
- , Ran Elkon
- & Reuven Agami
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| Open AccessProliferating versus differentiating stem and cancer cells exhibit distinct midbody-release behaviour
During cell division, a cytoplasmic bridge—the midbody—forms between the nascent daughter cells, but it has been unclear under which conditions this is retained by a daughter cell or released. Now, Ettinger and colleagues show that midbody-release occurs more frequently in stem cells compared with cancer cells.
- Andreas W. Ettinger
- , Michaela Wilsch-Bräuninger
- & Wieland B. Huttner
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p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression
Cellular senescence is characterized by the cessation of cell growth and the expression of the p16 protein. In this study, inhibition or loss of p300, a histone acetyltransferase, is shown to result in senescence that occurs independently of p16 and is associated with histone hypoacetylation and altered replication timing.
- Alexandre Prieur
- , Emilie Besnard
- & Jean-Marc Lemaitre
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Plasmonic substrates for multiplexed protein microarrays with femtomolar sensitivity and broad dynamic range
Protein microarrays are useful both in basic research and also in disease monitoring and diagnosis, but their dynamic range is limited. By using plasmonic gold substrates with near-infrared fluorescent enhancement, Tabakman et al. demonstrate a multiplexed protein array with improved detection limits and dynamic range.
- Scott M. Tabakman
- , Lana Lau
- & Hongjie Dai
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Regulation of MITF stability by the USP13 deubiquitinase
MITF is a transcription factor required for melanocyte development, which is activated in some melanomas. Zhao and colleagues show that USP13 removes ubiquitin from MITF, stabilizes MITF protein levels and enhances colony formation, suggesting that USP13 may be a therapeutic target in melanoma.
- Xiansi Zhao
- , Brian Fiske
- & David E Fisher
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| Open AccessToxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells
Polo-like kinase 1 is a key regulator of mitosis and is a candidate for drug development to treat cancer. Here, reduced expression of polo-like kinase 1 in adult mice has a minor impact on animal physiology, suggesting that polo-like kinase 1 inhibitors may be useful in the killing of tumour cells while sparing normal cells.
- Monika Raab
- , Sven Kappel
- & Klaus Strebhardt
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| Open AccessFunctional and molecular interactions between ERK and CHK2 in diffuse large B-cell lymphoma
Chk2 is a kinase that is a potential chemotherapeutic target. Here, Chk2 and the kinase ERK are shown to functionally interact, and are elevated in expression in human diffuse B-cell lymphomas. Combinatorial inhibition of the kinases was also shown to block tumour growth in anin vivomouse model.
- Bojie Dai
- , X. Frank Zhao
- & Ronald B. Gartenhaus
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Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site
The sigma-2 receptor is used as a biomarker for tumour cell proliferation but its identity is unknown. Using a novel radiolabelled probe, the authors identify progesterone receptor membrane component 1, which is overexpressed in several tumour types, as the putative sigma-2 receptor.
- Jinbin Xu
- , Chenbo Zeng
- & Robert H. Mach
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Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome
Mutations in the DNA helicaseBLM cause Bloom syndrome, which is characterized by slow replication fork progression and genetic instability. Here, cells lacking BLMare shown to have a defect in cytidine deaminase, which alters the pyrimidine pool and results in replication fork progression with altered velocity.
- Pauline Chabosseau
- , Géraldine Buhagiar-Labarchède
- & Mounira Amor-Guéret
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MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma
α-fetoprotein is used as a biomarker of hepatocellular cancer but the mechanisms that lead to its elevated expression are unknown. Kojimaet al.show that microRNA122 and CUX1 are important for the regulation of α-fetoprotein and suggest that loss of microRNA122 leads to more aggressive liver cancer.
- Kentaro Kojima
- , Akemi Takata
- & Kazuhiko Koike
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Article
| Open AccessTRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer
TGFβ can function as both a tumour suppressor and tumour promoter under different cellular contexts. Here, the cleavage product of the TGFβ type I receptor is shown to be generated in a TGFβ-dependent manner, and can induce the expression of genes involved in tumour cell invasion.
- Yabing Mu
- , Reshma Sundar
- & Marene Landström
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Article
| Open AccessIKKβ regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways
IKK kinases activate nuclear factor-κB, and the activated form of this transcription factor is found in endothelial cells in diseased tissue. In this study, mice lacking IKKβ in the endothelium are generated, and it is shown that defects in endothelial cell function are both IKK kinase activity dependent and independent.
- Noboru Ashida
- , Sucharita SenBanerjee
- & Anthony Rosenzweig
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α-Mannosidase 2C1 attenuates PTEN function in prostate cancer cells
PTEN is a phosphatase that regulates the phosphatidylinositol-3 kinase signalling pathway and is inactivated in many tumour types. Heet al.show that a mannosidase, α-mannosidase 2C1, can inactivate PTEN in prostate cancer cells, and that PTEN-positive human prostate tumours overexpress α-mannosidase 2C1.
- Lizhi He
- , Catherine Fan
- & Damu Tang
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Article
| Open AccessRapid cell-surface prion protein conversion revealed using a novel cell system
The study of prion diseases has been hampered as there is no method to distinguish newly formed abnormal prion protein conformers. Here, the authors describe a method to study newly formed abnormal prion protein and demonstrate that it is produced within 1 minute of cell exposure to prions.
- R. Goold
- , S. Rabbanian
- & S.J. Tabrizi
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Article
| Open AccessThe deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility
Deubiquitinating enzymes are involved in multiple cellular processes, including cell viability. The authors reveal a role for the deubiquitinating enzyme, USP17, in the migration of cells in response to chemokines and show that USP17 is required for the relocalization of GTPases involved in cell motility.
- Michelle de la Vega
- , Alyson A. Kelvin
- & James A. Johnston
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| Open AccessIntestinal epithelial stem cells do not protect their genome by asymmetric chromosome segregation
It has been proposed that stem cells use nonrandom chromosome segregation to avoid the accumulation of replication-induced mutations. Here, the authors examine intestinal epithelial stem cell division and show, using label exclusion and retention assays, that the cells segregate their chromosomes randomly.
- Marion Escobar
- , Pierre Nicolas
- & Catherine Legraverend
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Article
| Open AccessInflammation driven by tumour-specific Th1 cells protects against B-cell cancer
Inflammation can result in the formation of tumours, but the immune system is also involved in the elimination of cancer cells. Here, the authors show that inflammation driven by tumour-specific CD4+T cells results in tumour regression and identify a list of cytokines associated with cancer prevention.
- Ole Audun Werner Haabeth
- , Kristina Berg Lorvik
- & Alexandre Corthay
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Human TSC2-null fibroblast-like cells induce hair follicle neogenesis and hamartoma morphogenesis
Mutations inTSC2 lead to the formation of benign tumours called hamartomas. In this study, using a mouse xenograft model, the authors demonstrate that fibroblasts from patients carrying TSC2mutations can induce keratinocytes to form both hair follicles and hamartoma-like growths with active mTOR signalling.
- Shaowei Li
- , Rajesh L. Thangapazham
- & Thomas N. Darling
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Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences
Microvesicles containing RNA are released from tumour cells. Here, the authors show that microvesicles released from tumour cells in culture have amplified levels of thec-Myconcogene, which is also found in the cell of origin, suggesting that microvesicles could be used as biomarkers.
- Leonora Balaj
- , Ryan Lessard
- & Johan Skog
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