Featured
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| Open AccessSynergistic effect of tumor chemo-immunotherapy induced by leukocyte-hitchhiking thermal-sensitive micelles
Targeting the adenosinergic pathway represents a therapeutic option to overcome tumor-induced immunosuppression. Here the authors design E-selectin-modified thermal-sensitive micelles loaded with doxorubicin and an adenosine A2 receptor antagonist to enhance chemotherapy-induced anti-tumor immune responses.
- Jing Qi
- , Feiyang Jin
- & Yongzhong Du
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Article
| Open AccessArsenene-mediated multiple independently targeted reactive oxygen species burst for cancer therapy
Multifunctional materials with a number of effects are important for dealing with the complex environment in cancer therapy. Here, the authors report on surface-oxidized arsenene nanosheets coated with polydopamine and cancer cell membrane as a multi theranostic tumour targeting cancer therapy.
- Na Kong
- , Hanjie Zhang
- & Xiaoyuan Ji
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Article
| Open AccessSimultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease
Finding therapeutic strategies for aggressive triple negative breast cancer (TNBC) is an important challenge in clinical practice. Here, the authors identify a multi-kinases inhibitor with antitumor activity and able overcome chemotherapy resistance of TNBC in vivo.
- Katsutoshi Sato
- , Amol A. Padgaonkar
- & E. Premkumar Reddy
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Article
| Open AccessCanine tumor mutational burden is correlated with TP53 mutation across tumor types and breeds
Genomic studies of canine tumours have been done for individual cancer types or dog breeds. Here the authors analyse canine tumour genomics data across multiple breeds and cancer types, finding that mutational burden is associated with TP53 mutations and that Golden Retrievers are enriched for particular signatures.
- Burair A. Alsaihati
- , Kun-Lin Ho
- & Shaying Zhao
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Article
| Open AccessChemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system
Here, the authors show structural, biochemical, and functional insights into the discovery of epichaperome‐ directed chemical probes for use in central nervous system diseases. Probes emerging from this work have translated to human clinical studies in Alzheimer’s disease and cancer.
- Alexander Bolaender
- , Danuta Zatorska
- & Gabriela Chiosis
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Article
| Open AccessThe integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer
The Integrated Stress Response (ISR) is a cytoprotective pathway upregulated in many cancers. Here the authors show that the activation of PERK/p-eIF2α arm of ISR enhances ERK phosphorylation through translation repression of DUSP6, thus resulting in KRAS-driven lung tumorigenesis.
- Nour Ghaddar
- , Shuo Wang
- & Antonis E. Koromilas
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Article
| Open AccessPRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma
Arginine methylation by PRMTs is dysregulated in cancer. Here, the authors use functional genomics screens and identify PRMT1 as a vulnerability in pancreatic ductal adenocarcinoma, and further show that PRMT1 regulates RNA metabolism and coordinates expression of genes in cell cycle progression, maintaining genomic stability and tumour growth.
- Virginia Giuliani
- , Meredith A. Miller
- & Timothy P. Heffernan
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Article
| Open AccessSubcellular localization of biomolecules and drug distribution by high-definition ion beam imaging
Multiplexed ion beam imaging can provide subcellular localisation information but with limited resolution. Here the authors report an ion beam imaging method with nanoscale resolution which they use to assess the subcellular distribution of cisplatin.
- Xavier Rovira-Clavé
- , Sizun Jiang
- & Garry P. Nolan
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Article
| Open AccessRETRACTED ARTICLE: AKT3-mediated IWS1 phosphorylation promotes the proliferation of EGFR-mutant lung adenocarcinomas through cell cycle-regulated U2AF2 RNA splicing
IWS1 regulates multiple steps in RNA metabolism, including RNA elongation and alternative RNA splicing. Here the authors show that AKT3 phosphorylates IWS1, which alters U2AF2 RNA splicing and promotes growth of lung adenocarcinomas via a Sororin/ERK-dependent pathway.
- Georgios I. Laliotis
- , Evangelia Chavdoula
- & Philip N. Tsichlis
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Article
| Open AccessThe genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets
Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) display heterogeneous clinical and genetic characteristics. Here, the authors investigate the mutational landscape of 85 aNEN by whole genome sequencing and identify distinct subpopulations, tumour mutational burden patterns, drivers and actionable somatic alterations.
- Job van Riet
- , Harmen J. G. van de Werken
- & Bianca Mostert
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Article
| Open AccessAn integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer
It is hypothesized that there are a number of tumor specific driver genes for metastatic prostate cancer. Here, the authors perform genome-wide CRISPRi screens and integrate these data with metastatic prostate cancer functional and clinical genomics data to show that KIF4A and WDR62 drive aggressive prostate cancer phenotypes.
- Rajdeep Das
- , Martin Sjöström
- & Luke A. Gilbert
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Article
| Open AccessBRCA2 binding through a cryptic repeated motif to HSF2BP oligomers does not impact meiotic recombination
BRCA2 and its interactor HSF2BP are required for meiotic recombination. Here, the authors define the interaction structurally, revealing that a repeat in BRCA2 binds two HSF2BP units, increasing the affinity. This region is, however, not essential for mouse meiosis.
- Rania Ghouil
- , Simona Miron
- & Alex N. Zelensky
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Article
| Open AccessAn umbrella review of the evidence associating diet and cancer risk at 11 anatomical sites
Diet and food intake have been associated with a risk of developing different types of cancer but individual nutritional epidemiology studies are prone to inherent bias. Here, the authors perform an umbrella review of meta-analyses of observational studies and show the level of evidence for associating food and nutrients to cancer risk.
- Nikos Papadimitriou
- , Georgios Markozannes
- & Konstantinos K. Tsilidis
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Article
| Open AccessNEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1
NEK2 is a serine-threonine kinase overexpressed in a variety of human cancers. Here the authors show that NEK2 controls the stability of PD-L1 by preventing its proteasome-mediated degradation and that NEK2 targeting restores anti-tumor immune responses in preclinical models of pancreatic cancer.
- Xiaozhen Zhang
- , Xing Huang
- & Tingbo Liang
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Article
| Open AccessRetinoblastoma from human stem cell-derived retinal organoids
Retinoblastoma is a heritable pediatric cancer driven by mutations in RB1. Here, the authors demonstrate the first patient derived model of retinoblastoma using iPSCs from patients with germline mutations in RB1.
- Jackie L. Norrie
- , Anjana Nityanandam
- & Michael A. Dyer
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Article
| Open AccessFunctional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome
Germline mutations in the DNMT3A gene can cause an overgrowth syndrome associated with behavioural and hematopoietic phenotypes. Here the authors describe a mouse model of this syndrome that recapitulates many of these features, including conserved alterations in DNA methylation in the blood cells of both species.
- Amanda M. Smith
- , Taylor A. LaValle
- & Timothy J. Ley
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Article
| Open AccessSTING suppresses bone cancer pain via immune and neuronal modulation
There is an unmet clinical need to develop therapies to alleviate metastatic bone pain, frequently observed in patients with advanced cancers. Here, using mouse models of bone cancer pain, the authors show that STING agonists not only suppress bone cancer tumor burden, but also attenuate bone pain and reduce cancer-induced bone destruction.
- Kaiyuan Wang
- , Christopher R. Donnelly
- & Ru-Rong Ji
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Article
| Open AccessGWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms
Circulating liver enzymes, like alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are highly heritable and predictive of disease. Here, the authors perform a genome-wide association study on ALT and AST, revealing a rare variant in SLC30A10 associated with elevated ALT and AST.
- Lucas D. Ward
- , Ho-Chou Tu
- & Paul Nioi
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Article
| Open AccessLineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival
Heterogeneity in leiomyosarcomas (LMS) makes treatment of the disease challenging. Here the authors analyze LMS heterogeneity and molecular LMS subtypes using genomics and transcriptomics, finding origins in distinct lineages and associations with survival, in addition to the early emergence of metastatic clones.
- Nathaniel D. Anderson
- , Yael Babichev
- & Adam Shlien
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Article
| Open AccessIdentification of 22 susceptibility loci associated with testicular germ cell tumors
Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.
- John Pluta
- , Louise C. Pyle
- & Christian Kubisch
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Article
| Open AccessOncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis
The role of regulatory cis-elements in carcinogenesis and metastasis in esophageal squamous cell carcinoma remains crucial. Here the authors investigate H3K27ac-marked active enhancer profiles and transcriptomes in different types of esophageal tissues and identify oncogenic events and potential therapeutic targets.
- Bo Ye
- , Dandan Fan
- & Yunbo Qiao
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Article
| Open AccessA human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade
The anti-tumour effect of immune checkpoint inhibitors is potentiated by CD137 agonists in preclinical models, but translation of these results to the clinical practice is hampered by toxicity. Authors describe here a human CD137xPD-L1 bispecific antibody with improved anti-cancer activity whilst maintaining low toxicity in non-human primates.
- Cecile Geuijen
- , Paul Tacken
- & Mark Throsby
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Article
| Open AccessStromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer
BRD4 has a pro-tumorigenic role but non-cell-autonomous mechanisms of BRD4 activation need to be elucidated. Here the authors unravel a mechanism by which CAFs activate BRD4 and induce resistance to BET inhibitors in cancer cells through IL6/IL8 signaling.
- Wenyu Wang
- , Yen-An Tang
- & Qiang Yu
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Article
| Open AccessRefractoriness of STING therapy is relieved by AKT inhibitor through effective vascular disruption in tumour
How STING agonists exert anti-tumour effects remains unclear. Here, the authors show that STING agonists suppress tumor growth of subcutaneous xenografts models inducing early apoptosis of endothelial cells through the TNFalpha-TNFR1 signaling, while in primary tumors, additional inhibition of AKT is required for efficient induction of apoptosis via the same pathway.
- Seung-hwan Jeong
- , Myung Jin Yang
- & Gou Young Koh
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Article
| Open AccessTEM8 marks neovasculogenic tumor-initiating cells in triple-negative breast cancer
Vasculogenic mimicry (VM) contributes to the development of triple-negative breast cancer. In this study, the authors show that TEM8 is expressed in VM-forming breast cancer stem cells and it promotes stemness and VM differentiation capacity through a RhoC/ROCK1/SMAD5 axis
- Jiahui Xu
- , Xiaoli Yang
- & Suling Liu
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Article
| Open AccessThe impact of site-specific digital histology signatures on deep learning model accuracy and bias
Deep learning models have been trained on The Cancer Genome Atlas to predict numerous features directly from histology, including survival, gene expression patterns, and driver mutations. Here, the authors demonstrate that site-specific histologic signatures can lead to biased estimates of accuracy for such models, and propose a method to minimize such bias.
- Frederick M. Howard
- , James Dolezal
- & Alexander T. Pearson
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Article
| Open AccessBiochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting
KRAS is commonly mutated at codon 12 in several cancer types, offering a unique opportunity for the development of neoantigen-targeted immunotherapy. Here the authors present a pipeline for the prediction, identification and validation of HLA class-I restricted mutant KRAS G12 peptides, leading to the generation of mutant KRAS-specific T cell receptors for adoptive T cell immunotherapy.
- Adham S. Bear
- , Tatiana Blanchard
- & Beatriz M. Carreno
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Article
| Open AccessInterplay and cooperation between SREBF1 and master transcription factors regulate lipid metabolism and tumor-promoting pathways in squamous cancer
The relevance and underlying molecular mechanisms of epigenetic regulation in squamous cell carcinomas (SCC) await further characterization. Here, the authors show a transcriptional regulatory loop involving SREBF1, TP63 and KLF5 driving tumourigenesis in SCC through fatty acid, ERBB and mTOR pathway regulation.
- Li-Yan Li
- , Qian Yang
- & De-Chen Lin
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Article
| Open AccessGlucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer
Glucocorticoids (GC) are reported to block cancer cell proliferation, but the mode of action is unclear. Here the authors show that glucocorticoid receptor activation induces cancer cell dormancy in lung cancer by regulating CDKN1C expression through a distal enhancer, and these dormant cells are addicted to IGF-1R signalling pathway.
- Stefan Prekovic
- , Karianne Schuurman
- & Wilbert Zwart
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Article
| Open AccessStructure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase
The small molecule DNMDP acts as a velcrin by inducing complex formation between phosphodiesterase PDE3A and SLFN12, which kills cancer cells that express sufficient levels of both proteins. Here, the authors present the cryo-EM structure of the DNMDP-stabilized PDE3A-SLFN12 complex and show that SLFN12 is an RNase. PDE3A binding increases SLFN12 RNase activity, and SLFN12 RNase activity is required for DNMDP-mediated cancer cell killing.
- Colin W. Garvie
- , Xiaoyun Wu
- & Heidi Greulich
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Article
| Open AccessThe HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling
Hypoxia plays a critical role in tumor progression including invasion and metastasis. Here, the authors screened several hypoxia inducible genes and identified the oncogenic role of MAFF in breast cancer metastasis and that it activates IL11/STAT3 pathway.
- Eui Jung Moon
- , Stephano S. Mello
- & Amato J. Giaccia
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Article
| Open AccessEngineered macrophages as near-infrared light activated drug vectors for chemo-photodynamic therapy of primary and bone metastatic breast cancer
Bone metastases are associated with poor prognosis in patients with breast cancer and limited therapeutic options. Here the authors exploit near-infrared light responsive macrophages for the tumor-selective delivery of oxaliplatin prodrug for chemo-photodynamic therapy of primary and bone metastatic breast cancer.
- Yanjuan Huang
- , Zilin Guan
- & Chunshun Zhao
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Article
| Open AccessLoss of fragile site-associated tumor suppressor promotes antitumor immunity via macrophage polarization
The role of common fragile site associated genes such as FATS in the immune system is unclear. Here the authors show that deletion of Fats in a mouse tumour model leads to reduced tumour growth and change of macrophage phenotype from an M2-like to M1-like function.
- Lijuan Zhang
- , Kai Zhang
- & Rongxin Zhang
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Article
| Open AccessSMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
SMARCA4 is commonly inactivated in lung and ovarian cancers. Here the authors show that SMARCA4-deficient tumours have significantly reduced levels of the histone demethylases KDM6s and a strong dependency on these demethylases for tumour growth, so that they are vulnerable to KDM6s inhibition.
- Octavio A. Romero
- , Andrea Vilarrubi
- & Montse Sanchez-Cespedes
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Article
| Open AccessSingle-cell microRNA sequencing method comparison and application to cell lines and circulating lung tumor cells
Technologies for small non-coding RNA sequencing at the single-cell level are less mature than for sequencing mRNAs. Here the authors evaluate available protocols for analysis of circulating lung cancer tumour cells.
- Sarah M. Hücker
- , Tobias Fehlmann
- & Stefan Kirsch
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Article
| Open AccessTargeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells
Kras is frequently mutated in lung cancer and two isoforms are generated via alternative splicing. Here, the authors show that the two isoforms have divergent roles in cancer stem cells and the main tumour cell population, which are regulated by hypoxia and endoplasmic reticulum stress.
- Wei-Ching Chen
- , Minh D. To
- & Allan Balmain
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Article
| Open AccessTSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism
Tuberous sclerosis complex (TSC) is a multiorgan disease that can lead to hyperactive mTORC1 due to deficient TSC1 or TSC2 protein function. Here, the authors find that despite high mTORC1 activity, TFEB localizes to the nucleus and drives lysosomal gene expression via a non-canonical Rag-dependent mechanism.
- Nicola Alesi
- , Elie W. Akl
- & Elizabeth P. Henske
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Article
| Open AccessMorphological screening of mesenchymal mammary tumor organoids to identify drugs that reverse epithelial-mesenchymal transition
The epithelial-mesenchymal transition (EMT) has been implicated in stem cell properties and therapeutic resistance in cancer. Here, the authors show organoids derived from mesenchymal breast cancers exhibit a spikey structure which can be reverted and exploited for screening drugs that reverse EMT.
- Na Zhao
- , Reid T. Powell
- & Jeffrey M. Rosen
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Article
| Open AccessExtracellular matrix protein-1 secretory isoform promotes ovarian cancer through increasing alternative mRNA splicing and stemness
Extracellular matrix protein 1 (ECM1) has been associated with cancer but the underlying molecular mechanisms are not clear. Here, the authors show that while ECM1b isoform is a tumour suppressor, the secreted isoform ECM1a promotes tumourigenesis and chemoresistance through increasing stemness and alternative mRNA splicing in ovarian cancer.
- Huijing Yin
- , Jingshu Wang
- & Gong Yang
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Article
| Open AccessHomozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine
The metabolite methylthioadenosine (MTA) inhibits PRMT5. Therefore, MTA accumulation due to MTA phosphorylase (MTAP) deletion has been proposed as a vulnerability for PRMT5-targeted therapy in cancer. Here, the authors show that MTA does not accumulate in MTAP-deficient cancer cells but is secreted and metabolized by MTAP-intact cells in the tumour microenvironment.
- Yasaman Barekatain
- , Jeffrey J. Ackroyd
- & Florian L. Muller
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Article
| Open AccessMultiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer
Mutations in 5’ untranslated regions (UTRs) have a functional role in gene expression in cancer. Here, the authors develop a sequencing-based high throughput functional assay named PLUMAGE and show the effects of these mutations on gene expression and their association with clinical outcomes in prostate cancer.
- Yiting Lim
- , Sonali Arora
- & Andrew C. Hsieh
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Article
| Open AccessmTORC1 activity regulates post-translational modifications of glycine decarboxylase to modulate glycine metabolism and tumorigenesis
An increase in glycine decarboxylase (GLDC) activity, a key enzyme for glycine catabolism, has been associated to tumourigenesis. Here, the authors show that mTORC1 activation induces GLDC deacetylation which impairs its ubiquitin-associated degradation leading to increased GLDC activity and tumourigenesis.
- Rui Liu
- , Lin-Wen Zeng
- & Shu Li
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Matters Arising
| Open AccessReply to: “Inconsistent prediction capability of ImmuneCells.Sig across different RNA-seq datasets”
- Donghai Xiong
- , Yian Wang
- & Ming You
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Article
| Open AccessWhole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape
The genomic characterisation of nasopharyngeal carcinoma (NPC) remains crucial. Here, the authors perform whole-genome sequencing for 70 NPCs with EBV gene expression, report the somatic alterations and EBV-mediated effects converging on NF-κB activation and immune escape and identify targetable homozygous MTAP deletions.
- Jeff P. Bruce
- , Ka-Fai To
- & Kwok-Wai Lo
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Article
| Open AccessCross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women
GWAS have enhanced our understanding for the genetic basis of breast cancer, but the majority of them were performed for European ancestry populations. Here, the authors use a cross-ancestry approach and report seven new variants associated with breast cancer risk among women of African ancestry.
- Babatunde Adedokun
- , Zhaohui Du
- & Dezheng Huo
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Article
| Open AccessSensitive detection of tumor mutations from blood and its application to immunotherapy prognosis
It is possible to call single-nucleotide variant (SNV) in cell-free DNA (cfDNA), but the accuracy of detection is often affected by low tumour cfDNA content. Here, the authors develop a method, cfSNV, and show that it can be used even for medium-coverage whole exome sequencing of cfDNA.
- Shuo Li
- , Zorawar S. Noor
- & Xianghong Jasmine Zhou
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Article
| Open AccessOncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia
SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin.
- Quentin Van Thillo
- , Jolien De Bie
- & Charles E. de Bock
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Article
| Open AccessEZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer
Although the TMPRSS2-ERG gene fusion is the most common alteration in human prostate cancer, its involvement in disease progression remains unclear. Here, the authors demonstrate that ERG is methylated by Enhancer of zest homolog 2 leading to enhanced transcriptional and oncogenic activity.
- Marita Zoma
- , Laura Curti
- & Giuseppina M. Carbone
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Article
| Open AccessAgonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma
Agonistic CD40 antibodies (αCD40) have broad immunostimulatory properties, however their efficacy in glioma remains unclear. Here the authors show that αCD40 promotes the formation of tertiary lymphoid structures but does not improve survival and impairs the response to immune checkpoint blockade in murine glioma models.
- Luuk van Hooren
- , Alessandra Vaccaro
- & Anna Dimberg
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