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| Open AccessKinesin-14 and kinesin-5 antagonistically regulate microtubule nucleation by γ-TuRC in yeast and human cells
Mitotic spindle assembly requires strict control of microtubule nucleation by γ-tubulin ring complexes. Olmsted et al. report that the kinesin-like proteins Pkl1 and Cut7 antagonistically regulate nucleation in fission yeast, and show that a Pkl1 peptide blocks spindle assembly in human cancer cells.
- Zachary T. Olmsted
- , Andrew G. Colliver
- & Janet L. Paluh
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Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression
Tumour-infiltrating lymphocytes (TILs) can be suppressed by the tumour, but how this occurs is not clear. Here the authors show that the miR-200 family, which suppresses epithelial–mesenchymal transition, also targets tumour cell PD-L1 and thereby intratumoral immunosuppression and metastasis.
- Limo Chen
- , Don L. Gibbons
- & F. Xiao-Feng Qin
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Mitochondrial defects trigger proliferation of neighbouring cells via a senescence-associated secretory phenotype in Drosophila
Simultaneous mitochondrial dysfunction and Ras activation, which is commonly observed in cancer cells, has been shown to trigger the proliferation of neighbouring tissues in Drosophila. Nakamura et al.reveal that this effect is driven by a DNA-damage-induced senescence-associated secretory phenotype.
- Mai Nakamura
- , Shizue Ohsawa
- & Tatsushi Igaki
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Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk
Mammographic density is a strong risk factor for breast cancer. Here, the authors identify several new loci associated dense area, non-dense area and percent density, and highlight a shared genetic basis for mammographic density and breast cancer.
- Sara Lindström
- , Deborah J. Thompson
- & Rulla M. Tamimi
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Vascular channels formed by subpopulations of PECAM1+ melanoma cells
Tumours acquire new vasculature through angiogenesis or through alternative pathways including the less understood vasculogenesis mimicry. Here the authors identify a vasculogenic mimicry-competent subpopulation of melanoma cells that expresses the vascular cell adhesion molecule PECAM1, but not VEGFR-2.
- James M. Dunleavey
- , Lin Xiao
- & Andrew C. Dudley
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| Open AccessRNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells
A subset of cancers maintains telomere length independently of telomerase by activating alternative lengthening of telomeres (ALT) pathways. Here the authors show that RNaseH1 modulates telomeric homologous recombination frequencies in ALT cells by regulating the levels of RNA–DNA hybrids between TERRA and telomeric DNA.
- Rajika Arora
- , Yongwoo Lee
- & Claus M. Azzalin
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| Open AccessGenome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25
Genome-wide association studies (GWAS) have revealed gene variants associated with breast cancer, but their association with breast cancer development in Latinas is not clear. Here, the authors carry out a GWAS of breast cancer in Latinas and identify a significant protective variant of Indigenous American origin in the 6q25 region.
- Laura Fejerman
- , Nasim Ahmadiyeh
- & Elad Ziv
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LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers
Leukaemia inhibitory factor (LIF) is a p53 target but its role in cancer is unclear. Here Hu et al.show that LIF confers chemoresistance in colorectal cancer cells by Stat3-mediated upregulation of inhibitor of DNA-binding 1, leading to MDM2 E3 ubiquitin ligase upregulation and p53 degradation.
- Haiyang Yu
- , Xuetian Yue
- & Wenwei Hu
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Inflammation-driven carcinogenesis is mediated through STING
Chronic inflammation is known to promote tumorigenesis, but the mechanisms underlying this are incompletely understood. Here, the authors show that several carcinogens induce DNA leakage into the cytoplasm, which activates STING-dependent cytokine production and inflammation-driven tumorigenesis.
- Jeonghyun Ahn
- , Tianli Xia
- & Glen N. Barber
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Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1
The RNA-binding proteins Lin28A and Lin28B are known to have key roles in a variety of pathological states including cancer, obesity and diabetes. Here the authors show that Lin28A and -B alter cancer metabolism through let-7-mediated upregulation of pyruvate dehydrogenase kinase 1.
- Xiaoyu Ma
- , Chenchen Li
- & Huafeng Zhang
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A prevalent cancer susceptibility APOBEC3A hybrid allele bearing APOBEC3B 3′UTR enhances chromosomal DNA damage
Human APOBEC3A (A3A) cytidine deaminase is an enzyme that can introduce mutations into chromosomal DNA. Here the authors examine the genotoxic potential of A3A and the related enzyme A3B, and show that a highly prevalent chimaeric A3A-A3B deletion allele has increased DNA damage potential.
- Vincent Caval
- , Rodolphe Suspène
- & Simon Wain-Hobson
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| Open AccessConcomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut
Metastasizing tumour cells undergo epithelial-to-mesenchymal transition. Using both bioinformatic and in vivo approaches, Chanrion et al.identify combined Notch activation and p53 inactivation as a potent inducer of this transition, and apply this to create a highly metastatic tumour model in mice.
- Maia Chanrion
- , Inna Kuperstein
- & Sylvie Robine
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Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis
The INO80 complex is involved in chromatin remodelling during transcription and has been implicated in DNA repair. Here, the authors establish a role for INO80 in normal DNA replication and reveal a mechanism that targets this remodeler to replication forks via BAP1 and H2A ubiquitination.
- Han-Sae Lee
- , Shin-Ai Lee
- & Jongbum Kwon
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| Open AccessABRO1 suppresses tumourigenesis and regulates the DNA damage response by stabilizing p53
The scaffold protein Abraxas brother 1 (ABRO1) accumulates in the nucleus after oxidative stress but its role in cellular responses to DNA damage has not been elucidated. Here the authors show that ABRO1 exerts its tumour suppressor activity by regulating p53 stability via USP7 deubiquitinase.
- Jianhong Zhang
- , Mengmeng Cao
- & Xiaoming Yang
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Calcium-dependent FAK/CREB/TNNC1 signalling mediates the effect of stromal MFAP5 on ovarian cancer metastatic potential
The prognostic significance of stromal cells in ovarian cancer has not been explored. Here the authors show that stromal microfibrillar-associated protein 5 (MFAP5) drives metastasis of ovarian cancer and represents a new a prognostic marker related to decreased survival.
- Cecilia S. Leung
- , Tsz-Lun Yeung
- & Samuel C. Mok
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An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability
CendR peptides, based on a C-terminal motif found in neuropilins, have been used to promote drug delivery to tumours by endocytosis. Pang et al. show that CendR peptides are taken up by a mechanistically distinct form of endocytosis that resembles macropinocytosis, and is stimulated by nutrient depletion.
- Hong-Bo Pang
- , Gary B. Braun
- & Erkki Ruoslahti
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Article
| Open AccessDiurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment
Glucocorticoids are released in a diurnal pattern. Here, the authors show that EGF receptor (EGFR) signalling is negatively regulated by glucocorticoids, and that EGFR inhibitor has stronger antitumour effects when administered during the resting phase, when glucocorticoids are low, offering potential optimization of cancer therapy regimens.
- Mattia Lauriola
- , Yehoshua Enuka
- & Yosef Yarden
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The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models
The oncogene MDM2 has been associated with breast cancer progression and metastasis. Here the authors report the identification of a small molecule that binds MDM2 and that induces its degradation, and that is effective in the treatment of a mouse model of breast cancer.
- Wei Wang
- , Jiang-Jiang Qin
- & Ruiwen Zhang
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Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis
Focal adhesion kinase (FAK) is frequently overexpressed in solid tumours. Here Batista et al.show that loss of FAK skews hematopoietic progenitors toward myeloid differentiation and promotes metastases, warning against the use of FAK inhibitors in anticancer therapies.
- Silvia Batista
- , Eleni Maniati
- & Kairbaan Hodivala-Dilke
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| Open AccessFunctional annotation of colon cancer risk SNPs
Previous studies identified genetic variants associated with colorectal cancer (CRC), but the functional consequences of these genetic risk factors remain poorly understood. Here, the authors report that CRC risk variants reside in promoters and enhancers and could increase colon cancer risk through gene expression regulation.
- Lijing Yao
- , Yu Gyoung Tak
- & Peggy J. Farnham
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Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma depend on the transcription factor C/EBPβ
Dendritic cells (DC) are known to promote cancer progression by suppressing antitumor immunity. Here, Rehm et al. describe a mechanism whereby lymphoma cells induce C/EBPβ activation in DCs, which in turn secrete cytokines that support the proliferation and survival of lymphoma cells.
- Armin Rehm
- , Marcel Gätjen
- & Uta E. Höpken
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A20 controls intestinal homeostasis through cell-specific activities
Aetiology of colitis is highly complex and incompletely understood. Here the authors show in mouse models that A20 deubiquitinase limits pro-inflammatory cytokine production in myeloid cells while inhibiting proapoptotic response to these cytokines in enterocytes, and that only upon losing both functions intestinal pathologies develop.
- Lars Vereecke
- , Sara Vieira-Silva
- & Geert van Loo
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| Open AccessComplex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer
Several patients with metastatic prostate cancer have been shown to harbour tumours with markedly high mutation rates. Here, the authors characterise hypermutation in advanced prostate cancer samples and show that these samples have somatic mismatch repair gene mutations and microsatellite instability.
- Colin C. Pritchard
- , Colm Morrissey
- & Peter S. Nelson
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Article
| Open AccessGlutamine deprivation stimulates mTOR-JNK-dependent chemokine secretion
Glutamine deprivation is currently being tested as a therapeutic strategy in cancer. Shanware et al.show that in cultured cells, glutamine deprivation stimulates IL-8 secretion by triggering endoplasmic reticulum stress, and suggest that the potential of this effect to influence tumour development should be examined.
- Naval P. Shanware
- , Kevin Bray
- & Robert T. Abraham
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Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation
Many tumours originate from cancer stem cells (CSCs), a small population of cells that display stem cell properties. Here Kanda and colleagues show that the lipid mediator, sphingosine-1 phosphate (S1P), enhances expansion of ALDH-positive CSCs via S1P receptor 3 (S1PR3) and subsequent Notch activation, providing a rationale for targeting S1PR3 in cancer.
- Naoya Hirata
- , Shigeru Yamada
- & Yasunari Kanda
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Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation
Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.
- Maya Ghoussaini
- , Stacey L. Edwards
- & Anna De Fazio
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Activation of diverse signalling pathways by oncogenic PIK3CA mutations
Mutations in PIK3CA, a catalytic subunit of PI3 kinase, are linked to deregulation of Akt-mTOR signalling in many cancers. Here, using a SILAC-based quantitative proteomic approach, the authors discover six new AKT1 substrates, including the actin regulator cortactin.
- Xinyan Wu
- , Santosh Renuse
- & Akhilesh Pandey
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Phenotypic characterization of missense polymerase-δ mutations using an inducible protein-replacement system
The essential nature of replicative polymerases has hampered the study of polymerase-δ mutations found in colorectal cancer cells. Here, using polymerase-δ mutations as a proof of principle, the authors present an inducible single vector system that replaces any endogenous gene with an RNAi-resistant mutant version.
- Medini Manohar Ghodgaonkar
- , Patrick Kehl
- & Josef Jiricny
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| Open AccessGenomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes
Malignant mixed Müllerian tumours are a rare and aggressive gynaecological cancer with poor 5-year survival rates. Here, the authors characterize the mutational landscape of carcinosarcomas and highlight the role of chromatin remodelling dysregulation in carcinosarcoma tumorigenesis.
- Siân Jones
- , Nicolas Stransky
- & Victor E. Velculescu
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TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling
TNF-α signalling regulates a range of pathophysiological functions including tumour growth, but its role in lymphatic metastasis is unclear. Here the authors show that TNF-α signalling stimulates lymphatic endothelial cell activity, lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling.
- Hong Ji
- , Renhai Cao
- & Yihai Cao
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Small-molecule Bax agonists for cancer therapy
A major proapoptotic mediator, Bax, is expressed in lung cancer and its activity can be regulated by phosphorylation. Here, the authors screen a library of compounds for their ability to alter the phosphorylation status of Bax and identify therapeutic candidates.
- Meiguo Xin
- , Rui Li
- & Xingming Deng
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Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex
Molecular details of the synergy between integrins and syndecans are poorly understood. Here, Fiore et al. show that syndecan-4 and α5β1integrin form a trimolecular complex with Thy-1 that exhibits ‘dynamic catch’ behaviour, in which force strengthens the synergistic binding and modulates signalling at the focal adhesion level.
- Vincent F. Fiore
- , Lining Ju
- & Thomas H. Barker
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Loss of IP3R-dependent Ca2+ signalling in thymocytes leads to aberrant development and acute lymphoblastic leukemia
Ca2+signalling pathways are known to influence T-cell development and T-cell leukemia progression. Here the authors show that deletion of all three inositol triphosphate receptor homologues in mice severely impairs T-cell development in the thymus and causes spontaneous T-cell acute lymphoblastic leukemia.
- Kunfu Ouyang
- , Rafael Leandro Gomez-Amaro
- & Ju Chen
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Article
| Open AccessHuman Tra2 proteins jointly control a CHEK1 splicing switch among alternative and constitutive target exons
RNA binding proteins are key regulators of alternative splicing. Here, Best et al. show that the human Tra2α and Tra2ß RNA binding proteins jointly contribute to the control of constitutive and alternative splicing events to regulate essential biological processes including the response to DNA damage.
- Andrew Best
- , Katherine James
- & David J. Elliott
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Article
| Open AccessThe landscape of kinase fusions in cancer
Kinases activated by gene fusions represent potentially important targets for the development of cancer drugs. Here, the authors develop a method for detecting gene fusion events in RNA sequencing data from The Cancer Genome Atlas and identify several novel recurrent fusions involving kinases.
- Nicolas Stransky
- , Ethan Cerami
- & Christoph Lengauer
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Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours
Wilms tumour is a common childhood cancer. Here, the authors use whole-exome sequencing in 44 Wilms tumours to characterize their mutational landscape and show that DICER1 and DROSHAmutations can suppress the biogenesis of tumour-suppressing microRNAs.
- Dinesh Rakheja
- , Kenneth S. Chen
- & James F. Amatruda
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| Open AccessEpigenetic silencing of miR-210 increases the proliferation of gastric epithelium during chronic Helicobacter pylori infection
Chronic infection with the bacterium Helicobacter pylori is associated with inflammation and increased risk of gastric cancer. Kiga et al. show that methylation and silencing of the microRNA gene miR-210is associated with infection in humans, and promotes proliferation of gastric epithelial cells in culture.
- Kotaro Kiga
- , Hitomi Mimuro
- & Chihiro Sasakawa
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Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis
Rab-controlled trafficking pathways have been implicated in tumourigenesis. Here the authors show that Rab37 suppresses metastasis by regulating the exocytosis of tissue inhibitor of metalloproteinase 1 to repress matrix metalloproteinase 9 and represents a novel prognostic marker for lung cancer.
- Chung-Han Tsai
- , Hung-Chi Cheng
- & Yi-Ching Wang
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Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer
Abundance of certain gut enterobacteria is correlated with inflammation and cancer development in humans, but the interplay between the three factors is unclear. Here the authors show that gut inflammation is required for bacteria-associated tumour development in mouse models.
- Janelle C. Arthur
- , Raad Z. Gharaibeh
- & Christian Jobin
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Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis
Metastases are known to preferentially spread through the lymphatic vessels. Here the authors uncover a self-reinforcing paracrine loop between breast cancer cells and lymphatic endothelial cells, which promotes seeding of cancer cells and angiogenesis in pre-metastatic niches but can be effectively blocked by repurposed therapeutic agents.
- Esak Lee
- , Elana J. Fertig
- & Aleksander S. Popel
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Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages
The role of cell division modes of basal and luminal epithelial cells in prostate development and tumorigenesis is unclear. Here, the authors show that while luminal cells contribute to development and tumorigenesis via symmetrical divisions, basal cells do so through asymmetric divisions.
- Jia Wang
- , Helen He Zhu
- & Wei-Qiang Gao
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Recurrent CDC25C mutations drive malignant transformation in FPD/AML
Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML) is characterized by abnormal platelet function and a high risk of haematological malignancies. Here, the authors report frequent CDC25Cmutations in FPD/AML patients and suggest that this gene may influence malignant transformation in FPD/AML.
- Akihide Yoshimi
- , Takashi Toya
- & Mineo Kurokawa
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ArhGAP30 promotes p53 acetylation and function in colorectal cancer
Tumour suppressor activity of p53 has been suggested to rely on acetylation of its C terminus. Here Wang and colleagues show that the Rho GTPase-activating protein ArhGAP30 is required for P300-mediated p53 acetylation and functional activation in colorectal cancer, and identify ArhGAP30 as a potential prognostic marker.
- Jilin Wang
- , Jin Qian
- & Jing-Yuan Fang
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Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis
Tumour angiogenesis is critical for tumour growth and metastasis but the mechanisms that promote the growth of new blood vessels by tumours are not completely clear. Here the authors show that overexpression of the transcription factor Twist1 in certain tumour cells can lead them to differentiate into endothelial cells.
- Hsiao-Fan Chen
- , Chi-Hung Huang
- & Kou-Juey Wu
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Autophagic degradation of the inhibitory p53 isoform Δ133p53α as a regulatory mechanism for p53-mediated senescence
p53-mediated replicative senescence is associated with downregulation of the inhibitory p53 isoform Δ133p42α. Horikawa et al.show that this downregulation is a result of specific targeting of Δ133p42α for autophagic degradation by the E3 ubiquitin ligase STUB1.
- Izumi Horikawa
- , Kaori Fujita
- & Curtis C. Harris
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Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women
Ovarian cancer is common among women and is the leading cause of death from gynaecological malignancies. Here the authors identify two previously unknown genetic variants that increase the risk of epithelial ovarian cancer in Han Chinese women.
- Kexin Chen
- , Hongxia Ma
- & Qingyi Wei
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Article
| Open AccessMyc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis
Myc has been implicated in the development of multiple types of cancer. Here, the authors explore the therapeutic potential and mechanism of action of Myc inhibition in mouse and human models of glioblastoma, an aggressive type of tumour that is often resistant to conventional therapy.
- Daniela Annibali
- , Jonathan R. Whitfield
- & Laura Soucek
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YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression
Lung adenocarcinomas can convert to squamous cell carcinomas, which is associated with cancer progression and therapy resistance. Here, Gao et al. identify YAP as an essential barrier for this phenotypic conversion through ZEB2-mediated DNP63 repression.
- Yijun Gao
- , Wenjing Zhang
- & Hongbin Ji
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Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations
For children with acute lymphoblastic leukaemia (ALL), those with Down syndrome (DS) have decreased survival compared with children without DS. Here, the authors use exome sequencing to characterise the mutational landscape of patients with both ALL and DS and highlight genes related to survival and relapse.
- Sergey I. Nikolaev
- , Marco Garieri
- & Stylianos E. Antonarakis
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