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| Open AccessROCK1 mechano-signaling dependency of human malignancies driven by TEAD/YAP activation
Crosstalk between the p53 and Hippo pathway has been reported in different physiological contexts. Here, the authors show that p53 DNA contact mutations upregulate TEAD/YAP transcription indirectly and transform cells via hyperactivation of RhoA/ROCK/actomyosin signaling.
- Davide Esposito
- , Ila Pant
- & Stuart A. Aaronson
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Article
| Open AccessStructural insights into the BRAF monomer-to-dimer transition mediated by RAS binding
RAF kinases are essential for RAS protein signalling but how RAS binding regulates dimerization and activation of RAF has remained unclear. Here, the authors report cryoEM structures that provide mechanistic insights into the RAS-mediated monomer-to-dimer transition of full-length BRAF.
- Juliana A. Martinez Fiesco
- , David E. Durrant
- & Ping Zhang
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Article
| Open AccessCanonical WNT signaling-dependent gating of MYC requires a noncanonical CTCF function at a distal binding site
Gene-gating of a MYC oncogenic super-enhancer (OSE) increases its expression in colon cancer cells in a poorly understood process. Here the authors show that MYC gating requires a CTCF binding site (CTCFBS) within the OSE that directs the stepwise trafficking of the OSE to the nuclear pore to facilitate increased nuclear export of MYC mRNA, which results in a growth advantage.
- Ilyas Chachoua
- , Ilias Tzelepis
- & Anita Göndör
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Article
| Open AccessMAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade
PI3K inhibitors have limited efficacy in triple negative breast cancer (TNBC). Here, the authors show that MAPK4 activates AKT independent of PI3K and thus promotes tumour growth in a subset of TNBC and that MAPK4 inhibition sensitizes to PI3K blockade in these tumours.’
- Wei Wang
- , Dong Han
- & Feng Yang
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Article
| Open AccessAssociation of mutation signature effectuating processes with mutation hotspots in driver genes and non-coding regions
In cancer, associations between mutational signatures and driver mutations have been proposed but not fully explored. Here, the authors develop sigDriver to find associations between mutational signatures and mutation hotspots in order to predict coding and non-coding driver mutations in pan-cancer genomics data.
- John K. L. Wong
- , Christian Aichmüller
- & Marc Zapatka
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Article
| Open AccessEZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation
While inhibition of the EZH2 methyltransferase activity has been used for targeting EZH2, its role in cancer progression remains unclear. Here, the authors use neuroblastoma and small cell lung carcinoma model systems and reveal the crosstalk between EZH2 and MYC(N) in the regulation of tumour formation.
- Liyuan Wang
- , Chan Chen
- & Guoliang Qing
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Article
| Open AccessInterleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia
Interleukin-7 receptor alpha (IL7Ra) is important for lymphoid cell development but its role in leukaemogenesis is not clear. Here, the authors generate a knock-in murine model to show that activating mutations in IL7Ra can initiate precursor B-cell acute lymphoblastic leukaemia.
- Afonso R. M. Almeida
- , João L. Neto
- & João T. Barata
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Article
| Open AccessGenetic fusions favor tumorigenesis through degron loss in oncogenes
The impact of genetic fusions on degrons, which are motifs for ubiquitin-mediated protein degradation, has not been fully explored. Here, the authors analyse fusion genes affecting degrons in pan-cancer genomics data, validate their functional impact and find enrichment for both internal and C-terminal degron losses.
- Jing Liu
- , Collin Tokheim
- & Wenyi Wei
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Article
| Open AccessSPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition
Geminin-Cdt1 plays essential roles in the regulation of DNA replication. Here the authors reveal that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP prevents DNA replication over-firing and genome instability by affecting Geminin ubiquitination.
- Jian Ma
- , Qing Shi
- & Haojie Huang
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Article
| Open AccessOncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity
The lipid composition of the plasma membrane defines the localisation of KRAS and its oncogenic function. Here the authors show that EFR3A binds to active KRAS to recruit PI4KA and alters the lipid composition of the plasma membrane to promote KRAS oncogenic signalling and tumorigenesis.
- Hema Adhikari
- , Walaa E. Kattan
- & Christopher M. Counter
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Article
| Open AccessAcquisition of aneuploidy drives mutant p53-associated gain-of-function phenotypes
Previous studies report that mutant p53 proteins have gain-of-function activities and cause oncogenic phenotypes. Herein, the authors engineered two isogenic epithelial cell lines to express wild-type or missense mutant p53 or be deficient for p53 protein and show that aneuploidy drives several of the GOF phenotypes previously ascribed to mutant p53.
- Lindsay N. Redman-Rivera
- , Timothy M. Shaver
- & Jennifer A. Pietenpol
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| 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 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 AccessRAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site
Oncogenic RAS mutants remain difficult to target with small molecules. Here, the authors show that RAS-binding Affimer proteins inhibit RAS signaling while binding diverse regions on the RAS surface, suggesting the potential to use Affimers as tools to identify new binding pockets and pharmacophores.
- Katarzyna Z. Haza
- , Heather L. Martin
- & Darren C. Tomlinson
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Article
| Open AccessRAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis
Chronic myelomonocytic leukaemia is classified as proliferative (pCMML) or dysplastic based on the white blood cell counts but biological differences are unclear. Here, the authors show genetic, transcriptomic and epigenomic differences between these two subtypes establishing that pCMML is RAS-pathway driven and that inhibiting RAS-driven PLK1 expression is a viable therapeutic target.
- Ryan M. Carr
- , Denis Vorobyev
- & Mrinal M. Patnaik
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Article
| Open AccessSelective and noncovalent targeting of RAS mutants for inhibition and degradation
Most oncogenic RAS mutants remain undruggable. Here, the authors developed monobodies that selectively recognize the active state of KRAS(G12V) and KRAS(G12C) and demonstrated their utility in inhibiting RAS functions through inhibition and degradation.
- Kai Wen Teng
- , Steven T. Tsai
- & Shohei Koide
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Article
| Open AccessThe long non-coding RNA MIR31HG regulates the senescence associated secretory phenotype
Senescence-associated secretory phenotype (SASP) involves secretion of factors such as pro-inflammatory cytokines. Here the authors show that MIR31HG regulates the expression and secretion of a subset of SASP components that induce paracrine invasion, through interaction with YBX1 and induction of IL1A translation.
- Marta Montes
- , Michal Lubas
- & Anders H. Lund
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Article
| Open AccessAutophagy of the m6A mRNA demethylase FTO is impaired by low-level arsenic exposure to promote tumorigenesis
RNA m6A demethylase FTO has oncogenic roles in cancers. Here the authors show that chronic low-level exposure of arsenic inhibits autophagic degradation of FTO, leading to FTO stabilisation and reduced m6A RNA methylation in keratinocytes and its subsequent malignant transformation.
- Yan-Hong Cui
- , Seungwon Yang
- & Yu-Ying He
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Article
| Open AccessAn ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability
Neuroblastoma (NB) is often driven by MYCN amplification. Here, the authors show that the most frequent genetic lesion, gain of 17q21-ter in NB leads to overexpression of ALYREF, which forms a complex with MYCN, regulating MYCN stability via the deubiquitinating enzyme, USP3.
- Zsuzsanna Nagy
- , Janith A. Seneviratne
- & Glenn M. Marshall
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Article
| Open AccessKRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation
The molecular details of the RAS-RAF interaction are still not fully understood. Here, the authors present crystal structures of wild-type and mutant KRAS in complex with the RAS-binding and membrane-interacting cysteine-rich domains of RAF1, and propose a model of the membrane-bound RAS-RAF complex.
- Timothy H. Tran
- , Albert H. Chan
- & Dhirendra K. Simanshu
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Article
| Open AccessRUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia
The fusion gene RUNX1/RUNX1T1 is oncogenic in acute myeloid leukemia. Here, the authors show that the fusion gene alters the transcriptional landscape of the cells by changing the structure of the 5’UTR, altering isoform expression, and controlling the expression of splicing factors.
- Vasily V. Grinev
- , Farnaz Barneh
- & Olaf Heidenreich
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Article
| Open AccessInteraction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma
Rhabdomyosarcomas are tumours blocked in myogenic differentiation, which despite the expression of master muscle regulatory factors, including MYOD, are unable to differentiate. Here, the authors show that SNAI2 is upregulated by MYOD through super enhancers, binds to MYOD target enhancers, and arrests differentiation.
- Silvia Pomella
- , Prethish Sreenivas
- & Myron S. Ignatius
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Article
| Open AccessAkt1 and dCIZ1 promote cell survival from apoptotic caspase activation during regeneration and oncogenic overgrowth
Although executioner caspase activation is considered terminal, some cells are capable of survival, suggesting additional regulation. Here, the authors show that cells in the Drosophila wing imaginal disc survive caspase activation via Akt1 and dCIZ1 and actively participate in tissue regeneration.
- Gongping Sun
- , Xun Austin Ding
- & Denise J. Montell
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Article
| Open AccessBroad genic repression domains signify enhanced silencing of oncogenes
Epigenetically altered genes can have a key role in cancer pathobiology but epigenetic signatures that distinguish oncogenes are not yet known. Here, the authors identify broad genic repression domains, defined by widespread H3K27me3 modification, as an epigenetic signature to provide mutation-independent information for discovery of potential oncogenes.
- Dongyu Zhao
- , Lili Zhang
- & Kaifu Chen
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Article
| Open AccessCombating acquired resistance to MAPK inhibitors in melanoma by targeting Abl1/2-mediated reactivation of MEK/ERK/MYC signaling
Resistance to BRAF/MEK inhibitors is a major impediment to long-term survival for patients with BRAF-mutant melanomas. Here, the authors show that ABL kinases drive resistance by promoting MEK/ERK reactivation and the FDA-approved ABL kinase inhibitor nilotinib prevents and overcomes resistance.
- Rakshamani Tripathi
- , Zulong Liu
- & Rina Plattner
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Article
| Open Accessc-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis
c-Myc and p53 operate in a negative feedback manner to maintain cellular homeostasis. Here, the authors report a long noncoding RNA, MILIP as a downstream target of c-Myc and that MILIP represses p53 to support tumorigenicity.
- Yu Chen Feng
- , Xiao Ying Liu
- & Lei Jin
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Article
| Open AccessChromatin modifier MTA1 regulates mitotic transition and tumorigenesis by orchestrating mitotic mRNA processing
Dsyregulation of mitosis-related alternative splicing in cancer cells is not well understood. Here, the authors show that cancer metastasis-associated antigen 1 (MTA1), an oncogenic chromatin associated protein, is an RNA-binding protein that regulates the alternative splicing and transcript abundance of mitosis regulators.
- Jian Liu
- , Chunxiao Li
- & Haili Qian
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Article
| Open AccessSex differences in oncogenic mutational processes
There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.
- Constance H. Li
- , Stephenie D. Prokopec
- & Christian von Mering
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Article
| Open AccessMutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome
p53 mutants can promote tumorigenesis by affecting fundamental cellular pathways and functions. In this study, the authors demonstrate a novel mutant-p53/HIF1α/miR-30d axis that impacts Golgi structure, trafficking, and secretion of proteins essential for tumor growth and metastasis.
- Valeria Capaci
- , Lorenzo Bascetta
- & Giannino Del Sal
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Article
| Open AccessCopper bioavailability is a KRAS-specific vulnerability in colorectal cancer
The oncogene KRAS is frequently mutated in cancer, including colorectal cancer. Here, using a cell-surface proteomics approach, KRAS-mutated colorectal cancer cells are shown to express high levels of the copper transporter ATP7A, which has an essential roles in cancer cell survival and proliferation.
- Léo Aubert
- , Neethi Nandagopal
- & Philippe P. Roux
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Article
| Open AccessMulti-faceted epigenetic dysregulation of gene expression promotes esophageal squamous cell carcinoma
The epigenetic landscape of esophageal squamous cell carcinoma (ESCC) at genome-wide high resolution is incompletely studied. Here, the authors performed an integrated multi-omics analysis of ESCC and non-tumor tissues to define the genome-wide methylome landscape and epigenetic alterations to uncover oncogenic drivers of ESCC.
- Wei Cao
- , Hayan Lee
- & Trever G. Bivona
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Article
| Open AccessAn OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate
OTX2 promotes tumour growth in Group 3 medulloblastoma. Here, the authors show that OTX2 regulates PAX3 to induce neural de-differentiation and promote tumourigenesis in Group 3 medulloblastoma.
- Jamie Zagozewski
- , Ghazaleh M. Shahriary
- & Tamra E. Werbowetski-Ogilvie
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Article
| Open AccessA cytoskeleton regulator AVIL drives tumorigenesis in glioblastoma
Genes that modulate the cytoskeleton have been associated with increased cell proliferation and migration. Here, the authors show that AVIL, an actin regulatory protein, is overexpressed in glioblastomas and mediates oncogenic effects through regulation of FOXM1 stability and LIN28B expression.
- Zhongqiu Xie
- , Pawel Ł. Janczyk
- & Hui Li
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Article
| Open AccessMYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies
Oncogene addiction is considered as a cancer cell-autonomous phenomenon, but can also influence the host immune system. Here the authors show that MYC-driven lymphomagenesis is associated with a block in the maturation and effector functions of natural killer cells as a mechanism of tumor escape from immunosurveillance.
- Srividya Swaminathan
- , Aida S. Hansen
- & Dean W. Felsher
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Article
| Open AccessOncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma
Ewing sarcoma is characterized by the fusion of EWSR1 and FLI1. Here, the authors show that EWSR1-FLI1 increases the activity of the developmental transcription factor SOX6, which promotes tumor growth but also increases sensitivity to oxidative stress.
- Aruna Marchetto
- , Shunya Ohmura
- & Thomas G. P. Grünewald
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Article
| Open AccessProteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas
Papillary thyroid cancer (PTC) is one of the most common type of endocrine malignancy. Here, the authors use proteogenomic approaches to analyse the primary tumour and lymph node metastases from a PTC patient and report an oncogenic RET fusion, and potential druggable targets from the ubiquitin signaling machinery for treating human PTCs.
- Aswini Krishnan
- , Jean Berthelet
- & Krishnaraj Rajalingam
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Article
| Open AccessCapturing the primordial Kras mutation initiating urethane carcinogenesis
Why the carcinogen urethane causes only lung tumours driven by a specific oncogenic mutation in just one Ras gene in mice is unclear. Here, the authors capture mutations immediately after urethane exposure and show that the sequence specificity of mutagenesis, transcriptional status, and Ras genetic loci may all contribute to this specificity.
- Siqi Li
- , David M. MacAlpine
- & Christopher M. Counter
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Article
| Open AccessCombined burden and functional impact tests for cancer driver discovery using DriverPower
Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.
- Shimin Shuai
- , Federico Abascal
- & Christian von Mering
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Article
| Open AccessExtensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D
Kras is often mutated in colorectal cancer but how this oncogenic mutation alters signalling pathways globally is undetermined. Here, the authors analyse how this mutation affects protein interaction networks and signal flow showing an extensive re‐wiring of signalling in response to KRas mutation
- Susan A. Kennedy
- , Mohamed-Ali Jarboui
- & Walter Kolch
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Article
| Open AccessAndrogen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer
SPINK1 upregulation is found in ~10–25% of prostate cancers. Here, they show that whilst SPINK1 is transcriptionally repressed by androgen receptor and its co-repressor REST, it is upregulated after androgen-deprivation therapy, which leads to neuroendocrine differentiation of prostate cancer cells.
- Ritika Tiwari
- , Nishat Manzar
- & Bushra Ateeq
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Article
| Open AccessMUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer
MUC1-C is overexpressed in castration-resistant prostate cancer and neuroendocrine prostate cancer. Here, the authors show that MUC1-C drives lineage plasticity through MYC and BRN2, inducing neuroendocrine features and stemness in prostate cancer.
- Yota Yasumizu
- , Hasan Rajabi
- & Donald Kufe
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Article
| Open AccessInterpreting pathways to discover cancer driver genes with Moonlight
Identification of cancer driver genes, especially those that can act as tumour suppressors or oncogenes depending on context, remains a challenge. Here, the authors introduce Moonlight, a tool that integrates multi-omic data to address this challenge and identify numerous dual-role cancer genes.
- Antonio Colaprico
- , Catharina Olsen
- & Elena Papaleo
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Article
| Open AccessMLL-AF9 initiates transformation from fast-proliferating myeloid progenitors
Not all mutated cells become malignant, suggesting additional requirements for transformation. Here, the authors track blood progenitors from normal to malignancy driven by MLL-AF9, revealing a subset of myeloid progenitors predisposed to transformation dependent on their normal cycling state.
- Xinyue Chen
- , Daniel B. Burkhardt
- & Shangqin Guo
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Article
| Open AccessASCL1 is a MYCN- and LMO1-dependent member of the adrenergic neuroblastoma core regulatory circuitry
Polymorphisms in LMO1 are associated with increased susceptibility to develop neuroblastoma. Here, the authors show that LMO1 directly induces the transcription factor ASCL1, which regulates the differentiation of neurons, demonstrating that ASCL1 is part of the adrenergic neuroblastoma core regulatory circuit.
- Lu Wang
- , Tze King Tan
- & Takaomi Sanda
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Article
| Open AccessAurora-A mediated phosphorylation of LDHB promotes glycolysis and tumor progression by relieving the substrate-inhibition effect
Aurora-A kinase is frequently over-expressed in tumours. Here, the authors show that it modulates the activity of lactate dehydrogenase B, resulting in enhanced glycolysis, bio-synthesis and tumour growth.
- Aoxing Cheng
- , Peng Zhang
- & Zhenye Yang
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Article
| Open AccessHeterogeneity and dynamics of active Kras-induced dysplastic lineages from mouse corpus stomach
How a precancerous form (dysplasia) becomes gastric cancer is unclear. Here, the authors assess the role of Kras activation in heterogenous dysplastic cells in murine stomach corpus organoids, identifying two dysplastic stem cell populations and show that MEK inhibition causes alterations in cell behavior.
- Jimin Min
- , Paige N. Vega
- & Eunyoung Choi
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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 AccessGREB1 induced by Wnt signaling promotes development of hepatoblastoma by suppressing TGFβ signaling
The mechanisms promoting hepatoblastoma (HB) progression through Wnt/β-catenin signaling are unclear. Here, the authors show that the Wnt/ β-catenin axis induces GREB1 expression and nuclear localization, and suppresses TGFβ pathway, and propose GREB1 as a therapeutic target in HB.
- Shinji Matsumoto
- , Taku Yamamichi
- & Akira Kikuchi
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Article
| Open AccessB1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis
Promyelocytic leukemia protein (PML) is the scaffolding protein that organizes PML nuclear bodies. Here the authors determine the crystal structure of a PML B1-box multimer and characterise the oligomerisation behaviour of the PML RBCC construct and show that disrupting B1-B1 interactions precludes promyelocytic leukemia leukemogenesis in transgenic mice.
- Yuwen Li
- , Xiaodan Ma
- & Guoyu Meng