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| Open AccessImmunostimulatory nanomedicines synergize with checkpoint blockade immunotherapy to eradicate colorectal tumors
Nanoparticles can stimulate tumour microenvironment to promote anti-tumour immunity. Here, the authors show that the combination of delivering drugs by a nanoscale coordination polymer and anti-PD-L1 is synergistic in treating murine colorectal cancer.
- Xiaopin Duan
- , Christina Chan
- & Wenbin Lin
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Article
| Open AccessMolecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions
Bronchial premalignant lesions can potentially progress to lung squamous cell carcinoma. Here, the authors profile bronchial biopsies from high-risk smokers by RNA sequencing and identify four molecular subtypes of premalignant lesions and an immune molecular signature that associates with lesion progression.
- Jennifer E. Beane
- , Sarah A. Mazzilli
- & Avrum E. Spira
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Article
| Open AccessK27-linked ubiquitination of BRAF by ITCH engages cytokine response to maintain MEK-ERK signaling
BRAF drives MEK/ERK activation to facilitate tumorigenesis. Here, the authors show that in response to pro-inflammatory cytokines, ITCH mediates a non-proteolytic ubiquitination and activation of BRAF, which in turn sustains MEK/ERK signaling to facilitate melanoma cell growth.
- Qing Yin
- , Tao Han
- & Lixin Wan
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Article
| Open AccessA chemical toolbox for the study of bromodomains and epigenetic signaling
Bromodomains are conserved protein interaction modules that recognize acetyl-lysine modifications. Here the authors present a set of 25 selective small molecule inhibitors covering 29 human bromodomain targets and comprehensively evaluate the selectivity of this probe-set.
- Qin Wu
- , David Heidenreich
- & Stefan Knapp
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Article
| Open AccessBRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors
Mutations of the SWI/SNF chromatin-remodeling complex member SMARCB1 can cause malignant rhaboid tumors. Here the authors report a BRD9-containing SWI/SNF subcomplex that lacks SMARCB1 and its requirement for the survival of rhaboid tumors.
- Xiaofeng Wang
- , Su Wang
- & Charles W. M. Roberts
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Article
| Open AccessCorrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL
In chronic lymphocytic leukemia (CLL), evolution is driven by transcriptional and epigenetic heterogeneity. Here, the authors integrate epigenomic analyses to show how intra-tumoral epigenetic diversity results in divergent chromatin states in CLL cells, increasing cell-to-cell transcriptional heterogeneity.
- Alessandro Pastore
- , Federico Gaiti
- & Dan A. Landau
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Article
| Open AccessMetabolic profiling of cancer cells reveals genome-wide crosstalk between transcriptional regulators and metabolism
Aberrant gene expression in cancer coincides with drastic changes in metabolism. Here, the authors combined metabolome, transcriptome and proteome data in 54 cancer cell lines to uncover a genome-scale network of associations between transcriptional regulators and metabolites.
- Karin Ortmayr
- , Sébastien Dubuis
- & Mattia Zampieri
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Article
| Open AccessAURKB as a target in non-small cell lung cancer with acquired resistance to anti-EGFR therapy
Non-small cell lung cancer with EGFR mutations are known to develop resistance to EGFR tyrosine kinase inhibitors. Here, the authors show AURKB activation to be associated with resistance in EGFR mutant lung cancer cells, and that AURKB is a therapeutic target in resistant tumours that lack the p.T790M or other acquired mutations.
- Jordi Bertran-Alamillo
- , Valérie Cattan
- & Miguel-Angel Molina-Vila
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Article
| Open AccessStem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment
Cancer stem cells (CSCs) comprise a putative population that can drive growth and resistance. Here, in glioblastoma models the authors show that rather than being a distinct clonal entity, the CSC population represents a plastic state adoptable by most cancer cells via reversible state transitions induced by the microenvironment.
- Anne Dirkse
- , Anna Golebiewska
- & Simone P. Niclou
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Article
| Open AccessPartially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation
In cancer, global DNA methylation loss and CpG island hypermethylation are commonly observed. Here, in breast cancer the authors find that hyper-variability of partially methylated domains is the prime source of DNA methylation variation and that these domains fuel CpG island hypermethylation.
- Arie B. Brinkman
- , Serena Nik-Zainal
- & Hendrik G. Stunnenberg
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Article
| Open AccessPDGFRα+ stromal adipocyte progenitors transition into epithelial cells during lobulo-alveologenesis in the murine mammary gland
The origin and source of mammary gland progenitors and how they interact with the adipose‐rich stroma is unclear. Here, the authors identify PDGFRα+ adipocyte progenitors in the murine mammary stroma as a mesenchymal cell lineage recruited into the expanding epithelium during development, hormone exposure and pregnancy.
- Purna A. Joshi
- , Paul D. Waterhouse
- & Rama Khokha
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Article
| Open AccessCDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation
Cdk12 is primarily involved in the regulation of DNA damage response (DDR) gene transcription as well as mRNA processing. Here, the authors demonstrate that CDK12 suppresses intronic polyadenylation, and that inhibition of this kinase primarily affects the expression of long genes with higher numbers of polyA sites, features common to many DDR genes.
- Malgorzata Krajewska
- , Ruben Dries
- & Rani E. George
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Article
| Open AccessGenome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.
- Manuel A. Ferreira
- , Eric R. Gamazon
- & Georgia Chenevix-Trench
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Article
| Open AccessMitochondria-specific drug release and reactive oxygen species burst induced by polyprodrug nanoreactors can enhance chemotherapy
Mitochondria are a source of reactive oxygen species, which can be exploited to induce the death of cancer cells. Here, the authors use nanoparticles that release camptothecin in a reactive oxygen species dependent manner, leading to cancer cell death.
- Wenjia Zhang
- , Xianglong Hu
- & Da Xing
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Article
| Open AccessTranscriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance
The relationship between autophagy and BRAF signalling is unclear. Here, the authors describe that BRAF inhibition induces the autophagy-lysosomal function in BRAF-mutant melanomas via modulation of the TFEB and ZKSCAN3 transcriptome, which downregulates TGF-β and suppresses melanoma progression.
- Shun Li
- , Ying Song
- & Chengyu Liang
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Article
| Open AccessMulti-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma
Esophageal squamous cell carcinoma (ESCC) is highly prevalent in China. Here, the authors carry out multi-region sampling of Chinese ESCC samples, and find recurrent ERBB4 mutations, BRCA1/2 variants, and amplification of CD274; together with high levels of genomic and T-cell receptor heterogeneity.
- Ting Yan
- , Heyang Cui
- & Yongping Cui
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Article
| Open AccessA requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant cancers
Cohesin complex mediates cohesion of sister chromatids and DNA loop formation. Here the authors show another role of cohesin in replication fork progression, suggesting a potential therapeutic strategy for cohesin-mutant cancers.
- Gourish Mondal
- , Meredith Stevers
- & David A. Solomon
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Article
| Open AccessGasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation
Gasdermins mediate lytic cell death by forming pores in the plasma membrane. Here the authors show that gasdermins also permeabilize mitochondrial membrane, thereby facilitating intrinsic apoptosis pathway, downstream of apoptotic (Gasdermin E) and inflammatory (Gasdermin D) caspase activation.
- Corey Rogers
- , Dan A. Erkes
- & Emad S. Alnemri
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Article
| Open AccessLung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition
The tumor suppressor GATA4 is frequently epigenetically silenced in lung cancer. In this study, Gao et al. demonstrate that GATA4 regulates the expression of TGFBR2 and that TGFRB1 inhibitors can synergise with chemotherapeutics to inhibit the growth of GATA4-deficient tumors in mice.
- Lei Gao
- , Yong Hu
- & Liang Chen
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Article
| Open AccessLineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm
Translocation of (6;8)(p21;q24), a recurrent abnormality of blastic plasmacytoid dendritic cell neoplasm, involves adjacent MYC and RUNX2 regions. Here, the authors show that the RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, promoting the development of this cancer.
- Sho Kubota
- , Kenji Tokunaga
- & Goro Sashida
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Article
| Open AccessMultimodal interference-based imaging of nanoscale structure and macromolecular motion uncovers UV induced cellular paroxysm
Methods to track molecular motion in eukaryotic cells mostly rely on fluorescent labels, transfection or photobleaching. Here the authors use multimodal partial wave spectroscopy to perform label-free live cell measurements of nanoscale structure and macromolecular motion with millisecond temporal resolution.
- Scott Gladstein
- , Luay M. Almassalha
- & Vadim Backman
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Article
| Open AccessCompetitive endogenous RNA is an intrinsic component of EMT regulatory circuits and modulates EMT
Competitive endogenous RNAs help to regulate biological processes by regulating miRNA activity levels. Here the author show TGFBI acts as a ceRNA for miR-21 in the epithelial-to-mesenchymal transition.
- Yuwei Liu
- , Mengzhu Xue
- & Peng Wang
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Article
| Open AccessDefective homologous recombination DNA repair as therapeutic target in advanced chordoma
Chordomas are rare bone tumors with limited therapeutic options. Here, the authors identify molecular alterations associated with defective homologous recombination DNA repair in advanced chordomas and report prolonged response in a patient treated with a PARP inhibitor, which later acquired resistance due to a newly gained PARP1 mutation.
- Stefan Gröschel
- , Daniel Hübschmann
- & Stefan Fröhling
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Article
| Open AccessA GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis
Clear-cell carcinomas are aggressive tumours characterised by high accumulation of lipids and glycogen. Here, the authors report that these cancers have a common vulnerability to GPX4 inhibition-induced ferroptosis and using CRISPR screen and lipodomic profiling, they identify HIF-2α- HILPDA axis promotes ferroptosis via enrichment of PUFA lipids.
- Yilong Zou
- , Michael J. Palte
- & Stuart L. Schreiber
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Article
| Open AccessBreast cancer quantitative proteome and proteogenomic landscape
Gene expression profiles can classify breast cancer into five clinically relevant subtypes. Here, the authors perform an in-depth quantitative profiling of the proteome of 45 breast tumors, and show they can recapitulate the transcriptome-based classifications and identify many potentially antigenic tumour-specific peptides.
- Henrik J. Johansson
- , Fabio Socciarelli
- & Janne Lehtiö
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Article
| Open AccessSpecific inhibition of splicing factor activity by decoy RNA oligonucleotides
Alternative splicing, critical for gene expression, is deregulated in many diseases. Here the authors develop decoy oligonucleotides to specifically downregulate splicing factors activity.
- Polina Denichenko
- , Maxim Mogilevsky
- & Rotem Karni
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Article
| Open AccessPerfluorocarbon regulates the intratumoural environment to enhance hypoxia-based agent efficacy
Hypoxia-based agents need permeable and hypoxic intratumour environment to be effective. Here, the authors show that perfluorocarbon nanoparticles promote increased permeability and sustained hypoxia to improve accumulation of hypoxia-based agents, and inhibit intratumour oxygen reperfusion.
- Wenguang Wang
- , Yuhao Cheng
- & Jinhui Wu
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Article
| Open AccessIdentification of the kinase STK25 as an upstream activator of LATS signaling
Hippo pathway inactivation plays a role in many cancers, although how tumor cells depress signaling is unclear. Here, Lim et al. identify STK25, which activates LATS in a manner distinct from other upstream kinases and is focally deleted from a range of human cancers.
- Sanghee Lim
- , Nicole Hermance
- & Neil J. Ganem
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Article
| Open AccessA NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma
Neuroblastoma includes adrenergic and mesenchymal cell types that can interconvert. Here, the authors show that this transdifferentiation is driven by a NOTCH feedforward loop that allows a swift transition between two semi-stable cellular states.
- Tim van Groningen
- , Nurdan Akogul
- & Johan van Nes
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Article
| Open AccessProteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia
High hyperploidy is a common feature in childhood B-cell precursor acute lymphoblastic leukemia. Here, the authors perform proteogenomic and Hi-C analyses of this leukemia and the ETV6/RUNX1 subtype and show that CTCF and cohesin expression are low in hyperdiploid cases and transcriptional dysregulation in relation to topologically associating domain borders in some of these cases.
- Minjun Yang
- , Mattias Vesterlund
- & Kajsa Paulsson
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Article
| Open AccessMERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression
Hyperactivation of Akt promotes tumorigenesis. Here, the authors show that SAV1, a member of Hippo signalling, interacts with Akt to suppress Akt activity and MERTK-mediated Akt phosphorylation relieves this suppression to facilitate Akt oncogenic activity in clear cell renal carcinomas.
- Yao Jiang
- , Yanqiong Zhang
- & Pengda Liu
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Article
| Open AccessTemporal dynamic reorganization of 3D chromatin architecture in hormone-induced breast cancer and endocrine resistance
In breast cancer, the 3D architecture of the genome can impact gene regulation. Here, the authors use tethered chromatin conformation profiling to investigate 3D chromatin structure in models of hormone-induced breast cancer and endocrine resistance, finding dynamic temporal reorganisation.
- Yufan Zhou
- , Diana L. Gerrard
- & Victor X. Jin
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Article
| Open AccessGut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5−/− mice
RNF5 is a ubiquitin ligase regulating ER stress response. Here the authors show that Rnf5 deficiency potentiates immune response against melanoma via altered microbiota, and isolate bacterial strains that confer the same phenotype to wild type mice.
- Yan Li
- , Roberto Tinoco
- & Ze’ev A. Ronai
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Article
| Open AccessCrizotinib-induced immunogenic cell death in non-small cell lung cancer
Certain chemotherapeutic agents can exert their anticancer effect through indirect immune-dependent mechanism. Here, the authors screen a library of tyrosine kinase inhibitors and show that crizotinib is an effective stimulator of immunogenic cell death and can potentiate the efficacy of immune checkpoint blockade.
- Peng Liu
- , Liwei Zhao
- & Guido Kroemer
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Article
| Open AccessA temporary indwelling intravascular aphaeretic system for in vivo enrichment of circulating tumor cells
Ex vivo methods of circulating tumor cell (CTC) isolation use small blood volumes, limiting sensitivity and introducing analytical inaccuracies. The authors describe a proof-of-concept study of an in vivo aphaeresis system that continuously collects CTCs from a peripheral vein over several hours.
- Tae Hyun Kim
- , Yang Wang
- & Daniel F. Hayes
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Article
| Open AccessOncogenic potential of truncated RXRα during colitis-associated colorectal tumorigenesis by promoting IL-6-STAT3 signaling
The truncated form of retinoid X receptor-alpha is found in cancer. Here, the authors show that this mutant receptor promotes colorectal tumorigenesis by activation of NF-κB in myeloid cells, leading to subsequent IL-6-induced STAT3 activation in intestinal epithelial cells, which can be suppressed by ligand K-80003.
- Xiaohong Ye
- , Hua Wu
- & Xiao-kun Zhang
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Article
| Open AccessWnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
The Wnt pathway regulates anti-tumour immunity in melanoma. Here, the authors show that, in lung adenocarcinoma, secretion of the ligand Wnt1 induces immune resistance by impairing the ability of dendritic cells to cross-prime T cells, and that blocking Wnt signalling enhances rejection of tumours by acting both on the cancer and immune cells.
- Dimitra Kerdidani
- , Panagiotis Chouvardas
- & Maria Tsoumakidou
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Article
| Open AccessPrimary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model
Dissemination of tumor cells from the primary site is an early event. Here, the authors show that the early disseminated tumor cells are actively cleared by the host cytotoxic T lymphocytes induced by the primary tumor and that infiltration of granulocytic myeloid-derived suppressor cells counteracts such immune protection and allow metastasis development.
- Raziye Piranlioglu
- , EunMi Lee
- & Hasan Korkaya
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Article
| Open AccessPiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice
Identification of cancer genes altered by non-genetic mechanisms in B-cell lymphoma is challenging. Here, the authors report the development of transposon tools to perform genome-wide recessive screens in vivo and validate identified putative tumor suppressor genes using a CRISPR/Cas9 validation platform.
- Julia Weber
- , Jorge de la Rosa
- & Roland Rad
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Article
| Open AccessA natural WNT signaling variant potently synergizes with Cdkn2ab loss in skin carcinogenesis
Cdkn2ab knockout mice develop skin tumours but this phenotype is lost on backcrossing of the mice. Here, the authors describe a genetic variant encompassing Wnt7b that synergises with Cdkn2ab loss and is required for tumour formation in these mice.
- Paul Krimpenfort
- , Margriet Snoek
- & Anton Berns
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Article
| Open AccessSpecialized dendritic cells induce tumor-promoting IL-10+IL-17+ FoxP3neg regulatory CD4+ T cells in pancreatic carcinoma
Pancreatic ductal adenocarcinoma is characterized by a highly immunosuppressive tumour microenvironment. Here, the authors show that specialized subsets of tumour-infiltrating dendritic cells induce distinct CD4+ T cell programs and specifically identify a CD103–CD11b+ subset which induces tumor-promoting FoxP3– Type-1 regulatory T cells.
- Rocky M. Barilla
- , Brian Diskin
- & George Miller
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Article
| Open AccessTargeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells
The presence of bivalent epigenetic active and repressive histone marks control lineage-specific differentiation in embryonic stem cells. Here, the authors reveal that bivalent marks repress the differentiation gene IHH in colorectal cancer-initiating cells, and can be targeted by EZH2 inhibition
- Evelyne Lima-Fernandes
- , Alex Murison
- & Catherine A. O’Brien
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Article
| Open AccessThe anti-cancer drugs curaxins target spatial genome organization
Curaxins are a recently discovered class of anti-cancer agents that disturbs DNA/histone interactions within. Here the authors provide evidence that curaxins affect the spatial genome organization and compromise enhancer-promoter communication necessary for expression of several oncogenes, including MYC.
- Omar L. Kantidze
- , Artem V. Luzhin
- & Sergey V. Razin
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Article
| Open AccessGenomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma
Burkitt lymphoma (BL) is the most common pediatric B-cell lymphoma. Here, within the International Cancer Genome Consortium, the authors performed whole genome and transcriptome sequencing of 39 sporadic BL, describing the landscape of mutations, structural variants, and mutational processes that underpin this disease how alterations on different cellular levels cooperate in deregulating key pathways and complexes.
- Cristina López
- , Kortine Kleinheinz
- & Reiner Siebert
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Article
| Open AccessAtypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor
H2B monoubiquitination is implicated in oncogenesis. Here, the authors show that UBR7 PHD finger is a H2BK120 monoubiquitin ligase that acts a tumour suppressor in breast cancer by suppressing gene expression for EMT, while promoting expression of CDH4 which restrain WNT/β-cat pathway.
- Santanu Adhikary
- , Deepavali Chakravarti
- & Chandrima Das
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Article
| Open AccessSulfisoxazole inhibits the secretion of small extracellular vesicles by targeting the endothelin receptor A
Extracellular vesicles are released from cells and permit communication between different cell types. Here, the authors identify that the FDA approved antibiotic sulfisoxazole, can block the release of these vesicles in breast cancer cells resulting in reduced cell growth in vitro and in vivo.
- Eun-Ju Im
- , Chan-Hyeong Lee
- & Moon-Chang Baek
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Article
| Open AccessFBXW2 suppresses migration and invasion of lung cancer cells via promoting β-catenin ubiquitylation and degradation
FBXW2 is an F-box protein that target substrates for degradation through SCF E3 ligase. Here, the authors show that FBXW2 suppresses lung cancer migration and invasion by promoting degradation of β-catenin and this is dependent on EGF-AKT1.
- Fei Yang
- , Jie Xu
- & Yi Sun
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Article
| Open AccessDiagnosis of fusion genes using targeted RNA sequencing
Rapid and accurate detection of fusion genes is important in cancer diagnostics. Here, the authors demonstrate that targeted RNA sequencing provides fast, sensitive and quantitative gene fusion detection and overcomes the limitations of approaches currently in clinical use.
- Erin E. Heyer
- , Ira W. Deveson
- & James Blackburn
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Article
| Open AccessAberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer
Era+ breast cancer patients often develop resistance to endocrine therapy. Here, the authors show that FGFR1 amplification is a resistance mechanism to CDK4/6 inhibitor and endocrine therapy and that combined treatment with FGFR, CDK4/6, and anti-estrogens is a potential therapeutic strategy in Era+ breast cancer tumors.
- Luigi Formisano
- , Yao Lu
- & Carlos L. Arteaga
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