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| Open AccessDegree and site of chromosomal instability define its oncogenic potential
Aneuploidy caused by chromosomal instability is frequently observed in cancer, but little is known about its contribution to tumor development. Here, the authors show that in the mouse intestine, the consequences of aneuploidy are exquisitely dependent on both its extent and anatomical location.
- Wilma H. M. Hoevenaar
- , Aniek Janssen
- & Nannette Jelluma
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Article
| Open AccessExploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy
Allelic losses occurring in cancer cells have been suggested as potential targets for therapy. Here, the authors show how recurring loss of heterozygosity of a drug metabolic gene in colorectal cancers can be exploited using a low molecular weight compound.
- Veronica Rendo
- , Ivaylo Stoimenov
- & Tobias Sjöblom
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Article
| Open AccessMinimal barriers to invasion during human colorectal tumor growth
Invasion is a critical step in tumor development. Here, in colorectal cancer, the authors show that multiclonal invasion of the muscularis mucosae is pervasive, suggesting that invasive capacity is not a significant bottleneck in the evolution of the disease.
- Marc D. Ryser
- , Diego Mallo
- & Darryl Shibata
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Article
| Open AccessInflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis
STEAP4 promotes the uptake of copper, and copper is known to be enhanced in cancer tissues. Here, the authors show that STEAP4 is induced by IL17, which is increased in inflamed tissues, consequently the increased copper levels activate NFκB signalling and suppression of apoptosis.
- Yun Liao
- , Junjie Zhao
- & Xiaoxia Li
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Article
| Open AccessMTR4 drives liver tumorigenesis by promoting cancer metabolic switch through alternative splicing
Aberrant alternative splicing has been shown to contribute to the tumorigenic processes. Here, the authors show that MTR4 is overexpressed in hepatocellular carcinoma and has a role in tumorigenesis through the modulation of the splicing of glycolytic genes PKM2 and GLUT1.
- Lili Yu
- , Jinchul Kim
- & Yang Xu
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Article
| Open AccessPhysical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis
Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.
- Nikos Papadimitriou
- , Niki Dimou
- & Neil Murphy
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Article
| Open AccessWhite blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer
Identifying patients that will respond to a particular therapy remains a key challenge in precision oncology. Here, in gastric cancer, the authors show that circulating tumour DNA can predict recurrence, provided that the signal from white blood cells is filtered out.
- Alessandro Leal
- , Nicole C. T. van Grieken
- & Victor E. Velculescu
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Article
| Open AccessTRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway
The unfolded protein response allows tumour cells to adapt to ER stress, and aberrant activation of Nrf2 confers cancer progression. Here, the authors show that TRIM25 is induced during ER stress and promotes tumour cell survival by targeting Keap1 for degradation, leading to Nrf2 activation.
- Yanfeng Liu
- , Shishi Tao
- & Liang Chen
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Article
| Open AccessExtreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer
Tumours that are deficient in mismatch-repair genes should, in theory, have higher evolvability. Here, the authors explore this theory in gastro-oesophageal tumours.
- Katharina von Loga
- , Andrew Woolston
- & Marco Gerlinger
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Article
| Open AccessArf1-mediated lipid metabolism sustains cancer cells and its ablation induces anti-tumor immune responses in mice
Cancer stem cells (CSC) have been shown as the origin for therapeutic resistance and patient relapse. Here, the authors show that targeting Arf1-mediated lipid metabolism in CSC induces cell death but also an immunogenic anti-cancer response.
- Guohao Wang
- , Junji Xu
- & Steven X. Hou
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Article
| Open AccessBCL9 provides multi-cellular communication properties in colorectal cancer by interacting with paraspeckle proteins
BCL9 is an activator of oncogenic Wnt/β-catenin. Here, the authors show a β-catenin independent function of BCL9 in a subtype of colorectal cancers, where it interacts with paraspeckle proteins to enhance the mRNA stability of calcium signalling and neural associated genes to promote communication with tumour cells and its microenvironment.
- Meng Jiang
- , Yue Kang
- & Ruben D. Carrasco
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Article
| Open AccessGastric squamous-columnar junction contains a large pool of cancer-prone immature osteopontin responsive Lgr5−CD44+ cells
Cancers arising from the gastric squamous-columnar junction have high incidence and are characterized by a poor prognosis. Here, the authors use genetic mouse models to show that loss of p53 and Rb1 expression results in preferential tumour development at the gastric squamous-columnar junction that contains a large pool of osteopontin responsive Lgr5-CD44+ cells.
- Dah-Jiun Fu
- , Lianghai Wang
- & Alexander Yu. Nikitin
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Article
| Open AccessLATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function
The autophagic and Hippo pathways are both well characterized contributors to cancer. Here, Tang et al show that LATS1, but not LATS2, negatively regulates autophagy by promoting Beclin1 ubiquitination, which restricts lethal autophagy induced by sorafenib treatment in cancer cells.
- Fengyuan Tang
- , Ruize Gao
- & Gerhard Christofori
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Article
| Open AccessPSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression
PSPC1 has a critical role in promoting EMT and metastasis. Here, the authors demonstrate that PSPC1 is the contextual determinant of the oncogenic switch of PTK6/β-catenin subcellular localizations to drive metastasis of hepatocellular carcinoma cells via a PSPC1/PTK6/β-catenin signaling.
- Yaw-Dong Lang
- , Hsin-Yi Chen
- & Yuh-Shan Jou
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Article
| Open AccessGenome-wide CRISPR screen identifies ELP5 as a determinant of gemcitabine sensitivity in gallbladder cancer
Gemcitabine is used to treat gallbaldder cancer but patient responses are variable. Here, the authors use a genome-wide CRISPR screen and identify the translational elongator protein ELP5 as a protein that is important for mediating gemcitabine-induced apoptosis.
- Sunwang Xu
- , Ming Zhan
- & Jian Wang
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Article
| Open AccessCharacterization of genetic subclonal evolution in pancreatic cancer mouse models
In pancreatic cancer the Kras and Trp53 transgene driven KPC mouse model is used to experimentally study disease processes. Here, the authors analyse tumour evolution within the KPC model, finding both linear and branched evolution and highlighting the utility of this model in mechanistic research of tumour evolution.
- Noushin Niknafs
- , Yi Zhong
- & Rachel Karchin
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Article
| Open AccessInflammation induced by incomplete radiofrequency ablation accelerates tumor progression and hinders PD-1 immunotherapy
Radiofrequency ablation is used to treat metastatic colorectal cancer. In this study, the authors show that incomplete ablation of tumours results in metastases and show in mouse models that the chemokine CCL2 recruits myeloid cells to the partially ablated tumours, which can block T cell function.
- Liangrong Shi
- , Junjun Wang
- & Weihua Liao
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Article
| Open AccessIdentification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma
Predicting the drug response of patients with cancer is crucial for implementing targeted therapy. Here, Su et al. make patient-derived cell lines and perform targeted sequencing and RNA-seq to identify CDKN2A/2B loss as a predictor of response to CDK4/6 inhibitors in esophageal squamous cell carcinoma.
- Dan Su
- , Dadong Zhang
- & Weimin Mao
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Article
| Open AccessDe novo compartment deconvolution and weight estimation of tumor samples using DECODER
Separating different cell compartments from bulk gene expression data can be challenging. Here the authors present DECODER, which can perform de novo deconvolutions on non-negative matrices including microarray, RNA-seq and ATAC-seq data sets.
- Xianlu Laura Peng
- , Richard A. Moffitt
- & Jen Jen Yeh
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| Open AccessGenome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC
Resistance to the tyrosine kinase inhibitor Sorafenib, which is the standard treatment for advanced hepatocellular carcinoma, is a major clinical challenge. Here, the authors show that phosphoglycerate dehydrogenase, a key enzyme in the serine synthesis pathway, drives sorafenib resistance.
- Lai Wei
- , Derek Lee
- & Chun-Ming Wong
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Article
| Open AccessThe TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer
In the treatment of pancreatic ductal adenocarcinoma (PDAC), comorbidities such as cachexia limit quality of life and survival. Here, the authors show TLR7/8 agonist R848 remodels host and tumour immune responses, promoting survival and attenuating cachexia in murine models of PDAC.
- Katherine A. Michaelis
- , Mason A. Norgard
- & Daniel L. Marks
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Article
| Open AccessmicroRNA arm-imbalance in part from complementary targets mediated decay promotes gastric cancer progression
Functional miRNAs derived from the 5p or 3p arm of some miRNA duplexes have opposite roles in cancer progression. Here, the authors show that oncogenic miR-574-5p has greater preference in aggressive gastric cancer as compared with miR-574-3p and this arm preference is partly dependent on complementary targets mediated miRNA decay.
- Zhengyi Zhang
- , Jingnan Pi
- & Jia Yu
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Article
| Open AccessGastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases
Gastroesophageal reflux disease (GERD) is a major risk factor for Barret’s esophagus (BE) and esophageal adenocarcinoma (EA). Here, An et al. report 25 genetic loci for GERD, many of which associate with BE and EA or with other traits such as BMI.
- Jiyuan An
- , Puya Gharahkhani
- & Stuart MacGregor
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Article
| Open AccessCD36 inhibits β-catenin/c-myc-mediated glycolysis through ubiquitination of GPC4 to repress colorectal tumorigenesis
CD36 is a membrane glycoprotein that has been shown to have tumour promoting or suppressor function depending on tumour type. Here, the authors address CD36 function in colorectal cancer and show it acts as a tumour suppressor by inhibiting B-catenin/myc signalling, resulting in downregulation of glycolysis.
- Yuan Fang
- , Zhi-Yong Shen
- & Yi Ding
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Article
| Open AccessMacrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry
Tumor associated macrophages are functionally and phenotypically heterogeneous. Here the authors describe the spatial distribution of distinct macrophage populations within regions of gastric cancer and probe their associations with clinical outcomes, gene signatures and PDL1 expression.
- Yu-Kuan Huang
- , Minyu Wang
- & Alex Boussioutas
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Comment
| Open AccessMicroenvironment meets lineage complexity in junctional tumorigenesis
Using a sensitizing genetic model, Moon and colleagues provide compelling data for a determinant role of microenvironment in tumorigenesis, and lend support to the notion that such influences can be pharmacologically dampened to reduce the onset of cancers.
- Wa Xian
- & Frank McKeon
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Article
| Open AccessComprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients
Activating oncogenic mutations in KRAS and NRAS are common in colorectal cancer, which is a heterogenous disease. Here, the authors show that the RAS mutation spectrum is markedly different between colon and rectal cancer, and also different based on age of diagnosis and microsatellite instability.
- Ilya G. Serebriiskii
- , Caitlin Connelly
- & Joshua E. Meyer
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Article
| Open AccessLncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc
lncRNA and cellular metabolism are frequently dysregulated in cancer. In this study, the authors discover the lncGLCC1 is increased in colorectal cancer cells under glucose starvation conditions and correlates with poor prognosis in this cancer.
- Jiayin Tang
- , Tingting Yan
- & Jing-Yuan Fang
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Article
| Open AccessGenomic signatures reveal DNA damage response deficiency in colorectal cancer brain metastases
The development of brain metastases is a lethal yet poorly understood event in the evolution of many cancers. Here, the authors perform whole-genome and whole-exome sequencing on matched normal, primary and metastatic tissue samples to explore the genomic features of brain metastases in colorectal cancer.
- Jing Sun
- , Cheng Wang
- & Yanhong Gu
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Article
| Open AccessPatient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma
Identifying driver genes in unstable, heterogenous tumour types can be challenging. Here, Mourikis, Benedetti, Foxall and colleagues present a machine learning algorithm to tackle this problem in esophageal adenocarcinoma.
- Thanos P. Mourikis
- , Lorena Benedetti
- & Francesca D. Ciccarelli
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Article
| Open AccessRelaxin gene delivery mitigates liver metastasis and synergizes with check point therapy
Activated hepatic stellate cells are associated with fibrosis and liver metastases. Here, the authors identify an endogenous role of relaxin in regulating the activation of hepatic stellate cells and report nanoparticle-mediated relaxin gene therapy to mitigate fibrosis and liver metastasis.
- Mengying Hu
- , Ying Wang
- & Leaf Huang
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Article
| Open AccessCell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium
KRASG12V and BRAFV600E are oncogenic mutations that activate ERK signalling. Here, the authors use single cell analysis in intestinal organoids and show that BRAFV600E activates ERK in all intestinal cell types, while KRASG12V induces ERK activation in only a subset of cells, depending on cell differentiation state.
- Raphael Brandt
- , Thomas Sell
- & Markus Morkel
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Article
| Open AccessIL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization
Mast cells within the tumor microenvironment have controversial roles. Here, the authors show, using genetic mouse models, that in gastric cancer, mast cells at the periphery of the tumors are activated via cancer cell produced-IL33 and promote tumorigenesis by recruiting macrophages within the tumors.
- Moritz F. Eissmann
- , Christine Dijkstra
- & Matthias Ernst
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Article
| Open AccessKrt5+/Krt15+ foregut basal progenitors give rise to cyclooxygenase-2-dependent tumours in response to gastric acid stress
Cellular extrinsic environmental factors contribute to tumour development. Here, the authors show that gastric acid stress stimulates tumour formation from a defined tumour-competent Krt5 + /Krt15 + foregut basal progenitor cell population.
- Hyeongsun Moon
- , Jerry Zhu
- & Andrew C. White
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Article
| Open AccessChromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers
In tumours aberrant epigenetic modifications can alter the transcriptional state. Here, the authors identify a common tumour-specific shift to transcriptional repression associated with DNA methylation and chromatin dysregulation at the transcription start site.
- Mizuo Ando
- , Yuki Saito
- & Joseph A. Califano
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Article
| Open AccessNucleoporin Nup155 is part of the p53 network in liver cancer
The nuclear pore complex (NPC) is known to regulate p53 signaling and this has mainly been linked to peripheral NPC subunits. Here the authors show that Nup155 from the NPC inner ring regulates the p53 pathway by controlling p21 translation while also being a target of p53-mediated repression.
- Kerstin Holzer
- , Alessandro Ori
- & Stephan Singer
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Article
| Open AccessAssociation analyses identify 31 new risk loci for colorectal cancer susceptibility
In colorectal cancer (CRC), finding loci associated with risk may give insight into disease aetiology. Here, the authors report a genome-wide association analysis in Europeans of 34,627 CRC cases and 71,379 controls, and find 31 new risk loci and 17 new risk SNPs at previously reported loci.
- Philip J. Law
- , Maria Timofeeva
- & Malcolm G. Dunlop
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Article
| Open AccessExcessive miR-25-3p maturation via N6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression
Cigarette smoke induces microRNA dysregulation in cancers. Here, the authors show that cigarette smoke promotes the maturation of oncogenic primary miR-25 due to METTL3 hypomethylation, and mature miR-25 suppresses PH domain leucine-rich repeat protein phosphatase 2, resulting in oncogenic AKT activation in pancreatic cancer.
- Jialiang Zhang
- , Ruihong Bai
- & Dongxin Lin
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Article
| Open AccessPromotion of growth factor signaling as a critical function of β-catenin during HCC progression
Aberrant Wnt/b-catenin signaling is thought to be a major driver of hepatocellular carcinoma. Here, the authors show that β-Catenin is predominantly integrated within the AJ complex during the early stages of this cancer and enhance EGFR signaling to promote tumour survival.
- Eunsun Kim
- , Amanda Lisby
- & Patrick Viatour
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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 AccessiRGD synergizes with PD-1 knockout immunotherapy by enhancing lymphocyte infiltration in gastric cancer
The therapeutic efficacy of adoptive T cell transfer is limited by their ability to infiltrate solid tumours. Here, the authors show that loading the tumor penetrating cyclic peptide iRGD on the cell surface of T cells enhances their ability to penetrate the tumour, resulting in enhanced efficacy in a mouse model of gastric cancer.
- Naiqing Ding
- , Zhengyun Zou
- & Baorui Liu
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Article
| Open AccessTargeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma
A subset of esophageal squamous cell carcinoma harbors dysregulated Fbxo4- cyclin D1 axis. Here, the authors show that the dysregulation of Fbxo4-cyclin D1 leads to mitochondrial dysfunction and glutamine addiction rendering these tumors susceptible to metabolic inhibitors even when resistant to CDK4/6 inhibitors.
- Shuo Qie
- , Akihiro Yoshida
- & J. Alan Diehl
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Article
| Open AccessABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield
The mechanisms underlying differential chemotherapeutic response to 5-fluorouracil are not fully known. Here, the authors show that ABDH5 regulates sensitivity to 5-fluorouracil in colorectal cancer by regulating lysosome function.
- Juanjuan Ou
- , Yuan Peng
- & Houjie Liang
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Article
| Open AccessIrreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer
Irreversible electroporation (IRE) has been approved as ablation therapy for pancreatic ductal adenocarcinoma (PDAC). Here, the authors show that, in mouse models, IRE reverses the immunosuppressive microenvironment of PDAC resulting in increased and durable response when combined with PD1 checkpoint inhibition therapy.
- Jun Zhao
- , Xiaofei Wen
- & Chun Li
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Article
| Open AccessMiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1
Pancreatic ductal adenocarcinoma must adapt to a nutrient-poor microenvironment. Here, the authors show that miR-135 accumulates in response to glutamine deprivation and inhibits aerobic glycolysis by targeting phosphofructokinase-1, thereby redirecting glucose carbon to the TCA cycle and allowing pancreatic cancer cells survival.
- Ying Yang
- , Mari B. Ishak Gabra
- & Mei Kong
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Article
| Open AccessLoss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer
Whether the Wnt enhanceosome’ components BCL9/9l can affect intestinal homeostasis and tumorigenesis is still unclear. Using conditional Bcl9/9l KO mice, the authors of this study show that the BCL9/9l complex is required for intestinal stem cells to drive tissue regeneration and that loss of BCL9/9l suppresses Wnt-driven transformation.
- David M. Gay
- , Rachel A. Ridgway
- & Owen J. Sansom
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Article
| Open AccessA recurrent cancer-associated substitution in DNA polymerase ε produces a hyperactive enzyme
Somatic alterations in the exonuclease domain of DNA polymerase ɛ have been linked to the development of highly mutated cancers. Here, the authors report that a major consequence of the most common cancer-associated Polɛ variant is a dramatically increased DNA polymerase activity.
- Xuanxuan Xing
- , Daniel P. Kane
- & Polina V. Shcherbakova
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Article
| Open AccessAberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming
There are distinct hypermethylation patterns in gene promoters in hepatocellular carcinomas (HCCs). Here, the authors show that the enhancer of C/EBPβ is recurrently hypomethylated in human HCCs, recapitulating this in a transgenic murine model and linking aberrant enhancer hypomethylation to hepatocarcinogenesis.
- Lei Xiong
- , Feng Wu
- & Ka-Fai To
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Article
| Open AccessExosomes harbor B cell targets in pancreatic adenocarcinoma and exert decoy function against complement-mediated cytotoxicity
The humoral immune response role in cancer is unclear. Here the authors perform an in-depth proteomic profiling of immunoglobulin-bound proteins in plasma from pancreatic ductal adenocarcinoma patients and find cancer-cell specific antibodies neutralized by binding to cancer-cell derived exosomes.
- Michela Capello
- , Jody V. Vykoukal
- & Samir M. Hanash