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| Open AccessMutant KRAS promotes malignant pleural effusion formation
Malignant pleural effusion (MPE) is a lethal condition associated with various cancers. Here, the authors show that cancer cells withKRASmutations promote MPE by recruiting myeloid cells via CCL2 signalling and that pharmaceutical targeting of KRAS results in reduced MPE incidence and volume in mouse models.
- Theodora Agalioti
- , Anastasios D. Giannou
- & Georgios T. Stathopoulos
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Article
| Open AccessRAF proteins exert both specific and compensatory functions during tumour progression of NRAS-driven melanoma
The melanoma-driver mutations in NRAS and BRAF are mutually exclusive but the contribution of RAF signalling downstream of NRAS remains to be clarified. Here, using mouse models, the authors show specific roles of each member of the RAF family at different stages of melanomagenesis.
- Coralie Dorard
- , Charlène Estrada
- & Sabine Druillennec
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Article
| Open AccessThe essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis
Yap is a transcriptional factor involved in tumorigenesis. Here the authors show that a previously unknown post-translational modification of Yap, O-GlcNAcylation, increases its transcriptional activity and is required for high glucose-induced liver cancer development.
- Xiao Zhang
- , Yongxia Qiao
- & Fenyong Sun
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Article
| Open AccessMenin enhances c-Myc-mediated transcription to promote cancer progression
Menin is a protein with context-dependent oncogenic or oncosuppressive roles; the oncogenic activity is mainly due to its function as a cofactor of the MLL1 histone methyltransferase complex. Here the authors show that Menin regulates c-Myc-dependent transformation independently of the MLL complex.
- Gongwei Wu
- , Mengqiu Yuan
- & Ping Gao
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Correspondence
| Open AccessCorrespondence: Reply to ‘Oncogenic MYC persistently upregulates the molecular clock component REV-ERBα’
- Anton Shostak
- , Bianca Ruppert
- & Michael Brunner
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Correspondence
| Open AccessCorrespondence: Oncogenic MYC persistently upregulates the molecular clock component REV-ERBα
- Brian J. Altman
- , Annie L. Hsieh
- & Chi V. Dang
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Article
| Open AccessEGFR/ARF6 regulation of Hh signalling stimulates oncogenic Ras tumour overgrowth
EGFR signalling is required for oncogenic Ras driven tumorigenesis. In this study, using aDrosophilatumour model the authors demonstrate that depletion of Arf6, a Ras-related GTP-binding protein activated by EGFR, supresses oncogenic Ras driven overgrowth via modulation of Hedgehog signalling.
- Chiswili Chabu
- , Da-Ming Li
- & Tian Xu
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Article
| Open AccessMutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma
Kras activation and p16 inactivation cooperatively promote pancreatic cancer progression. Here, the authors show that such cooperation depends upon an increased expression of the NAD(P)H oxidase NOX4 achieved through transcription factors independently regulated by the two oncogenic genetic alterations.
- Huai-Qiang Ju
- , Haoqiang Ying
- & Paul J. Chiao
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Article
| Open AccessAn integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer
KRAS-driven cancers remain refractory to current clinical therapies. In this study, the authors show that lung and pancreatic cancers expressing oncogenic KRAS can be targeted by genetic inhibition of FOSL1, which involves downregulation of genes of the mitotic machinery.
- Adrian Vallejo
- , Naiara Perurena
- & Silve Vicent
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Article
| Open AccessMicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells
SMAD7 is a transcriptional target and a negative regulator of TGFβ signalling forming a negative feedback loop. Here the authors show that in cancer cells TGFβ activates the expression of microRNA-182 that suppresses SMAD7 protein, promoting TGFβ-mediated breast tumour invasion and bone metastasis.
- Jingyi Yu
- , Rong Lei
- & Guohong Hu
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Article
| Open AccessNQO1 inhibits proteasome-mediated degradation of HIF-1α
Elevated levels of the oxidoreductase NQO1 in tumours are associated with poor prognosis but how this contributes to cancer is poorly understood. Here, the authors find that NQO1 competes with PHD proteins, resulting in the stabilization of the hypoxia induced transcription factor HIF-1α.
- Eun-Taex Oh
- , Jung-whan Kim
- & Heon Joo Park
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Article
| Open AccessIRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation
IRS proteins are scaffolds that can activate survival signalling pathways. In this study, the authors identified IRS4 as a potential oncogene in breast cancer that leads to the constitutive activation of PI3K/AKT signalling and thus confers resistance to HER2-targeted therapy.
- Gerjon J. Ikink
- , Mandy Boer
- & John Hilkens
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Article
| Open AccessGenetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer
Genome-wide association studies have identified multiple loci associated with the risk of developing renal cancer. Here, the authors show that one of these loci generates open chromatin, which enhances the binding of HIF and HIF-mediated transactivation ofMYC.
- Steffen Grampp
- , James L. Platt
- & Johannes Schödel
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Article
| Open AccessIncreased global transcription activity as a mechanism of replication stress in cancer
Cancer cells proliferate at high rates and incur replication stress. Here, the authors show that this can be the consequence of oncogene-induced higher transcriptional activity, which, through increased RNA synthesis and R-loop accumulation, results in replication fork slowing and DNA damage.
- Panagiotis Kotsantis
- , Lara Marques Silva
- & Eva Petermann
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Article
| Open AccessBimodal antagonism of PKA signalling by ARHGAP36
Protein kinase A (PKA) is a key mediator of cyclic AMP signalling. Here, Eccles et al. show that ARHGAP36 antagonizes PKA by acting as a kinase inhibitor and targeting the catalytic subunit for endolysosomal degradation, thus reducing sensitivity of cells to cAMP and promoting Hedgehog signalling.
- Rebecca L. Eccles
- , Maciej T. Czajkowski
- & Oliver Rocks
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Article
| Open AccessSatellite RNAs promote pancreatic oncogenic processes via the dysfunction of YBX1
Satellite RNAs are aberrantly transcribed during pancreatic cancer progression. Here, the authors show that major satellite RNA binds to the multifunctional protein YBX1 in the cytoplasm and induces mutations in nuclear and mitochondrial DNA by preventing YBX1 stress-induced intracellular translocation.
- Takahiro Kishikawa
- , Motoyuki Otsuka
- & Kazuhiko Koike
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Article
| Open AccessStromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
The risk of developing cancer increases with age. Here, the authors address the contribution of age-dependent accumulation of senescent cells within the tumour stroma compartment and show that senescent cells increase the infiltration of myeloid-derived suppressor cells that inhibit cytotoxic T-cells, thus facilitating tumour outgrowth.
- Megan K. Ruhland
- , Andrew J. Loza
- & Sheila A. Stewart
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Article
| Open AccessIdentification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia
The fusion of two genes during the pathogenesis of cancer can create oncogenes. In this study, the authors screen pediatric B-cell precursor acute lymphoblastic leukaemia samples for the presence of fusion genes and describe fusion genes that define new molecular subtypes of the disease
- Henrik Lilljebjörn
- , Rasmus Henningsson
- & Thoas Fioretos
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Article
| Open AccessIntermolecular biparatopic trapping of ErbB2 prevents compensatory activation of PI3K/AKT via RAS–p110 crosstalk
Targeted therapy of ErbB2-dependent tumours often provokes an adaptive response leading to reactivation of the PI3K/AKT pathway. Here the authors identify an ErbB3-independent compensatory mechanism comprising Ras/PI3K activation directly by ErbB2, and develop biparatopic panErbB inhibitors to block this mode of resistance.
- Rastislav Tamaskovic
- , Martin Schwill
- & Andreas Plückthun
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Article
| Open AccessThe oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy
Cancer cells have previously been shown to be addicted to glutamine and glutaminase enzyme activity. Here, the authors show that overexpression of the JUN proto-oncogene in breast cancer cells regulates glutaminaseexpression and is sufficient to confer sensitivity to glutaminase-targeted therapy.
- Michael J. Lukey
- , Kai Su Greene
- & Richard A. Cerione
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Article
| Open AccessBcl-2 is a critical mediator of intestinal transformation
The anti-apoptotic protein Bcl-2 is selectively expressed in intestinal stem cells (ISCs). Here, the authors show that, in intestinal stem cells, Bcl-2 alleviates apoptotic priming induced by the loss of the tumour suppressor Apc in ISCs and that the absence of Bcl-2 or pharmacological blockade of Bcl-2 can inhibit the intestinal tumorigenesis driven by the Apc-loss.
- Maartje van der Heijden
- , Cheryl D. Zimberlin
- & Louis Vermeulen
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Defective Hfp-dependent transcriptional repression of dMYC is fundamental to tissue overgrowth in Drosophila XPB models
C-terminal mutations in the XPB helicase subunit of TFIIH are associated with cancer. Here, using Drosophilamodels, the authors demonstrate C-terminally truncated Hay/XPB alleles enhance overgrowth dependent on Hfp, the orthologue of the MYC transcriptional repressor FIR.
- Jue Er Amanda Lee
- , Naomi C. Mitchell
- & Leonie M. Quinn
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Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities
Mutations in the tumour suppressor p53 can produce a protein that has additional functions. Here, the authors describe gain of function mutants of p53 that induce the expression of genes involved in nucleotide metabolism, which increases the activity of GTPases and results in invasion and metastasis.
- Madhusudhan Kollareddy
- , Elizabeth Dimitrova
- & Luis A. Martinez
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Article
| Open AccessDevelopmental-stage-dependent transcriptional response to leukaemic oncogene expression
Acute myeloid leukaemia often originates from a chromosomal translocation creating a RUNX1/ETO fusion protein. Here Regha et al, generate a mouse stem cell model and demonstrate the fusion protein disrupts transcription in a differentiation-stage-specific manner.
- Kakkad Regha
- , Salam A. Assi
- & Constanze Bonifer
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Article |
Oncogenes create a unique landscape of fragile sites
Aberrant oncogene expression can cause replication stress leading to chromosomal breaks. Here the authors map the chromosomal break loci induced by two different oncogenes and by a replication inhibitor, and show that each treatment induces a unique pattern of breaks in the same cell type.
- Karin Miron
- , Tamar Golan-Lev
- & Batsheva Kerem
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Article
| Open Access3D hotspots of recurrent retroviral insertions reveal long-range interactions with cancer genes
Retroviral insertional mutagenesis is used for identifying genes involved in the development of cancer. Here, the authors overlay cancer-causing insertions with genome-wide Hi-C data and find that retroviral elements tend to cluster in 3D hotspots.
- Sepideh Babaei
- , Waseem Akhtar
- & Jeroen de Ridder
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Article
| Open AccessIntracellular CD24 disrupts the ARF–NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation
P53 is a tumour suppressor that is frequently mutated or downregulated in cancer. Here, Wang et al. show that CD24, a molecule frequently overexpressed in cancer, promotes p53 degradation by disrupting a regulatory ARF–MDM2 interaction, and silencing CD24 prevents the downregulation of p53.
- Lizhong Wang
- , Runhua Liu
- & Yang Liu
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Article
| Open AccessZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling
Driver mutations in early T-cell precursor leukaemia (ETP-ALL) are poorly characterized. Here the authors show that Zeb2overexpression is often found in ETP-ALL, can recapitulate the disease in transgenic mice and confers survival advantage by upregulating IL-7 signalling.
- Steven Goossens
- , Enrico Radaelli
- & Jody J. Haigh
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Helicobacter pylori CagA promotes Snail-mediated epithelial–mesenchymal transition by reducing GSK-3 activity
Gastric cancer is associated with H. pylori infection and these tumours frequently show features of epithelial–mesenchymal transition (EMT). Here, the authors show that the H. pylorivirulence protein, CagA, reduces the activity of GSK3b, which leads to the stabilization of Snail, a protein that induces EMT.
- Da-Gyum Lee
- , Hyun Sil Kim
- & Yong Chan Lee
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Article |
Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism
ErbB2 is a receptor tyrosine kinase that localizes to the plasma membrane. Dinget al. now show that ErbB2 also localizes to mitochondria, where it regulates mitochondrial respiratory function and resistance to cancer chemotherapy.
- Yan Ding
- , Zixing Liu
- & Ming Tan
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Article |
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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Article |
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