Featured
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| 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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Article
| Open AccessIL-4 together with IL-1β induces antitumor Th9 cell differentiation in the absence of TGF-β signaling
CD4+ helper T cells producing IL-9 (Th9) have been implicated in anti-tumor immunity, with Th9 differentiation inducible in vitro via IL-4 and TGFβ treatment. Here the authors show that replacing TGFβ with IL-1β induces a distinct IL-9+ CD4+ population that have strong cytotoxic and anti-tumor activity in preclinical mouse models.
- Gang Xue
- , Guangxu Jin
- & Yong Lu
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Article
| Open AccessBone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT
Allogeneic hematopoietic cell transplantation is the standard treatment of acute myeloid leukemia, but many patients relapse. Here the authors show increased markers of exhaustion and cancer antigen specificity within bone marrow-residing memory T cells precede and potentially predict the relapse.
- Maddalena Noviello
- , Francesco Manfredi
- & Chiara Bonini
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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 AccessBcor loss perturbs myeloid differentiation and promotes leukaemogenesis
BCL6 corepressor (BCOR) is recurrently mutated in acute myeloid leukaemia and myelodysplastic syndrome. Here, the authors use mouse models to show the mechanism of how inactivation of BCOR in haematopoietic stem cells contributes to the development of leukaemia.
- Madison J. Kelly
- , Joan So
- & Lev M. Kats
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Article
| Open AccessDissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications
Malignant pleural mesothelioma (MPM) is a rare and aggressive form of cancer. Here, the authors show MPM is heterogeneously composed of epithelioid and sarcomatoid components and their proportions associate with prognosis and could inform therapeutic strategies.
- Yuna Blum
- , Clément Meiller
- & Didier Jean
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Article
| Open AccessSpatial-fluxomics provides a subcellular-compartmentalized view of reductive glutamine metabolism in cancer cells
Measuring metabolic fluxes in cellular compartments is a challenge. Here, the authors introduce an approach to infer fluxes in mitochondria and cytosol, and find that IDH1 is the major producer of cytosolic citrate in HeLa cells and that in SDH- deficient cells citrate synthase functions in reverse.
- Won Dong Lee
- , Dzmitry Mukha
- & Tomer Shlomi
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Article
| Open AccessChiral DNA sequences as commutable controls for clinical genomics
Any DNA sequence can be represented by a chiral partner sequence – an exact copy arranged in reverse nucleotide order. Here, the authors show that chiral DNA sequence pairs share important properties and show the utility of synthetic chiral sequences (sequins) as controls for clinical genomics.
- Ira W. Deveson
- , Bindu Swapna Madala
- & Tim R. Mercer
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Article
| Open AccessBromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma
Liposarcoma (LPS) is a rare cancer that can acquire resistance to chemotherapy. Here, the authors map super-enhancers in LPS, finding BET-protein dependent mechanisms that can be targeted by a BET protein degrader, which also can overcome acquired resistance to chemotherapy in LPS.
- Ye Chen
- , Liang Xu
- & H. Phillip Koeffler
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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 AccessA serum microRNA classifier for the diagnosis of sarcomas of various histological subtypes
Sarcomas are rare malignant tumours of bone and soft tissue whose diagnosis remain difficult. Here, the authors analyse serum samples from over 1000 patients and using separate discovery, training and validation cohorts, identify and validate a 7-microRNA index that distinguishes malignant sarcomas from benign disease.
- Naofumi Asano
- , Juntaro Matsuzaki
- & Takahiro Ochiya
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Article
| Open AccessMultiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer
ABCB1 encodes Multidrug Resistance Protein which promotes efflux of chemotherapeutic and targeted agents. Here, in breast and ovarian cancer the authors identify multiple transcriptional fusion partners involving ABCB1 that are associated with treatment failure and previous treatment regimens.
- Elizabeth L. Christie
- , Swetansu Pattnaik
- & David D. L. Bowtell
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Article
| Open AccessER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression
T-cell function impairment is one of the major determinants of tumour immune evasion. Here, the authors show that the hostile conditions in the tumour microenvironment lead to C/EBP homologous-protein upregulation in T cells via ER stress, resulting in repression of T-bet and consequent inhibition of CD8+ T cell function.”
- Yu Cao
- , Jimena Trillo-Tinoco
- & Paulo C. Rodriguez
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Article
| Open AccessReversible histone glycation is associated with disease-related changes in chromatin architecture
Proteins continuously undergo non-enzymatic modifications such as glycation, which accumulate under physiological conditions but can be enhanced in disease. Here the authors characterise histone glycation, provide evidence that it affects chromatin, particularly in breast cancer, and identify DJ-1 as a deglycase.
- Qingfei Zheng
- , Nathaniel D. Omans
- & Yael David
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Article
| Open AccessH3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
Lysine27-to-methionine mutations in histone H3 genes (H3K27M) occur in a subgroup of gliomas and decrease genome-wide H3K27 trimethylation. Here the authors utilise primary H3K27M tumour lines and isogenic CRISPR-edited controls and show that H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3.
- Ashot S. Harutyunyan
- , Brian Krug
- & Jacek Majewski
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Article
| Open AccessClonal architectures predict clinical outcome in clear cell renal cell carcinoma
Clear cell renal cell carcinoma (ccRCC) is a urogenital cancer with a well-defined genetic landscape. Here, the authors analyse the clonal architecture of ccRCC patients from three populations, and find prognostic subtypes linked to immune infiltrates and clonal architecture.
- Yi Huang
- , Jiayin Wang
- & Baifeng Zhang
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Article
| Open AccessGeneric synthesis of small-sized hollow mesoporous organosilica nanoparticles for oxygen-independent X-ray-activated synergistic therapy
A common failure of many cancer treatments is attributed to the resistance imparted by tumour hypoxia. Here, the authors report on the generic synthesis of small-sized hollow mesoporous organosilica nanoparticles which are designed for oxygen-independent X-ray-activated synergistic therapy.
- Wenpei Fan
- , Nan Lu
- & Xiaoyuan Chen
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Article
| Open AccessPhototrophic purple bacteria as optoacoustic in vivo reporters of macrophage activity
Current optoacoustic probes for cancer imaging have limitations including background noise, long-term toxicity and scarce imaging depth in living tissue. Here the authors use Rhodobacter, purple bacteria rich in bacteriochlorophyll a, as an optoacoustic reporter to image tumor-associated macrophages in mice in vivo.
- Lena Peters
- , Ina Weidenfeld
- & Andre C. Stiel
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Article
| Open AccessFacile syntheses of conjugated polymers for photothermal tumour therapy
Conjugated polymers are of interest for photothermal applications; however, synthesis of these polymers can be complex. Here, the authors report on a facile synthesis method that uses a modified CBT-Cys click reaction to make conjugated polymers and test these polymers for photothermal therapy applications.
- Peiyao Chen
- , Yinchu Ma
- & Gaolin Liang
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Article
| Open AccessA KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma
Super enhancers are frequently involved in the dysregulation of gene expression in cancer. Here, in kidney cancer, a super enhancer is shown to drive the expression of KLF6, which alters the expression of lipid metabolism genes and promotes tumorigenesis.
- Saiful E. Syafruddin
- , Paulo Rodrigues
- & Sakari Vanharanta
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Article
| Open AccessApoptotic tumor cell-derived microRNA-375 uses CD36 to alter the tumor-associated macrophage phenotype
The mode of miRNA transfer between tumour-immune cells is usually via exosomes. Here, the authors show that an alternative mode of transfer whereby miR-375 from apoptotic tumour cells can be transferred to tumour-associated macrophages via CD36 receptor, which induces macrophage migration and infiltration to the tumours.
- Ann-Christin Frank
- , Stefanie Ebersberger
- & Bernhard Brüne
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Article
| Open AccessThe Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy
Lung cancer patients who smoke show a better response to immunotherapy than non-smokers. Here, the authors show that tobacco smoke induces PD-L1 expression on lung epithelial cells via AhR that is associated with benefits of PD-1 inhibitor in patients, shedding new lights on lung carcinogenesis and immunotherapy.
- Gui-Zhen Wang
- , Li Zhang
- & Guang-Biao Zhou
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Article
| Open AccessDeciphering the complex role of thrombospondin-1 in glioblastoma development
Thrombospondin-1 (THSB1) is a component of the ECM with a role in regulating cancer development and tumour vasculature. Here, the authors show that TGF-beta-induced THBS1 expression contributes to the invasive behaviour of GBM cells and promotes resistance to antiangiogenic therapy partially through interaction with CD47.
- Thomas Daubon
- , Céline Léon
- & Andréas Bikfalvi
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Article
| Open AccessBioengineered bacterial vesicles as biological nano-heaters for optoacoustic imaging
Bacterial outer membrane vesicles (OMVs) are increasingly used as carriers for drug delivery. Here the authors encapsulate biopolymer melanin into OMVs, extending their use to optoacoustic imaging both in vitro and in vivo, and demonstrate the potential of this tool for photothermal therapy applications.
- Vipul Gujrati
- , Jaya Prakash
- & Vasilis Ntziachristos
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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 AccessRegnase-1-mediated post-transcriptional regulation is essential for hematopoietic stem and progenitor cell homeostasis
Regnase-1 is known to mediate post-trasncriptional regulatory activity through degradation of target mRNAs. Here, the authors show that Regnase-1 regulates self-renewal of haematopoietic stem and progenitor cells through modulation of the stability of Gata2 and Tal1 mRNA.
- Hiroyasu Kidoya
- , Fumitaka Muramatsu
- & Nobuyuki Takakura
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Article
| Open AccessACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis
ACVR1 and H3.1K27M mutations co-occur in diffuse intrinsic pontine glioma. Here, the authors generate a mouse model that recapitulates these genetic lesions and show, using genetic and pharmacological approaches, that the bone morphogenetic protein pathway may be a therapeutic target in these tumours.
- Christine M. Hoeman
- , Francisco J. Cordero
- & Oren J. Becher
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Article
| Open AccessThe SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression
Tumor cell-microenvironment interactions generate heterogeneity and promote progression. Here, Ma et al. show that the E3 ligase SIAH2 degrades NRF1 in response to hypoxia to enhance pro-tumor metabolic and environmental effects, whereas NRF1 stabilization sensitizes tumor cells to apoptosis.
- Biao Ma
- , Hongcheng Cheng
- & Quan Chen
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Article
| Open AccessPocket similarity identifies selective estrogen receptor modulators as microtubule modulators at the taxane site
Taxanes are natural products which bind beta-tubulin, stabilize microtubules and have a broad spectrum of anticancer activity. Here authors employ a computational binding site similarity screen and cell-based assays to reveal a SERM cross-reactivity between the estrogen receptor and the beta-tubulin taxane binding pocket.
- Yu-Chen Lo
- , Olga Cormier
- & Russ B. Altman
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Article
| Open AccessDeep convolutional neural networks for accurate somatic mutation detection
Somatic mutations are crucial to the understanding of cancer genesis, progression, and treatment, but are still challenging to detect. Here the authors present NeuSomatic, a convolutional neural network approach for accurate somatic mutation detection across various sequencing scenarios.
- Sayed Mohammad Ebrahim Sahraeian
- , Ruolin Liu
- & Hugo Y. K. Lam
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Article
| Open AccessTyrosine phosphorylation activates 6-phosphogluconate dehydrogenase and promotes tumor growth and radiation resistance
6-phosphogluconate dehydrogenase is commonly upregulated in cancers. Here, the authors show that activation of EGFR induces phosphorylation of this enzyme at Y481 to activate the pentose phosphate pathway, which consequently reduces ROS and accelerates DNA synthesis to promote tumor growth and radioresistance.
- Ruilong Liu
- , Wenfeng Li
- & Weiwei Yang
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Article
| Open AccessA network-centric approach to drugging TNF-induced NF-κB signaling
Chemical perturbation of specific protein–protein interactions is notoriously difficult, yet necessary when complete inhibition of a signalling pathway is detrimental to the cell. Here, the authors use a systems approach and identify two first-in-class small molecules that specifically inhibit TNF-induced NF-κB activation.
- Nicolas A. Pabon
- , Qiuhong Zhang
- & Robin E. C. Lee
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Article
| Open AccessG-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma
ATRX deficiency is linked to genomic stability in cancer cells. Here, the authors show that ATRX inactivation induces G-quadruplex formation, leading to genome-wide DNA damage, and the use of G-quadruplex stabilisers can be exploited therapeutically in ATRX deficient gliomas.
- Yuxiang Wang
- , Jie Yang
- & Jason T. Huse
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Article
| Open AccessCounting growth factors in single cells with infrared quantum dots to measure discrete stimulation distributions
Measuring growth factors in single cells at physiologically relevant stimulation doses is challenging. Here the authors use fluorescent quantum dots and calibrated three-dimensional deconvolution microscopy to digitally count growth factors in single cells and reveal stimulation distributions in cancer cells.
- Phuong Le
- , Sung Jun Lim
- & Andrew M. Smith
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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 AccessInducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses
Lack of respiratory complex I is a hallmark of oncocytomas. Here the authors show that inactivation of this complex via knockout of the NDUFS3 subunit or using metformin, converts tumors from an aggressive phenotype into low-proliferative oncocytomas, which can be further inhibited by targeting pro-tumorigenic macrophages.
- Ivana Kurelac
- , Luisa Iommarini
- & Giuseppe Gasparre
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Article
| Open AccessOverexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner
Oncogene-induced replication stress (RS) promotes cancer development. Here, the authors report that cancer cells adapt to oncogene-induced RS by overexpressing downstream components of ATR-CHK1 pathway, Claspin and Timeless, which have protective role at the replication forks independent of their checkpoint function.
- Julien N. Bianco
- , Valérie Bergoglio
- & Philippe Pasero
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Article
| Open AccessTargeting MC1R depalmitoylation to prevent melanomagenesis in redheads
Melanocortin-1 receptor is a palmitoylated protein and variants of the receptor are associated with red hair colour and susceptibility to melanoma. Here, the authors describe a method to enhance the palmitoylation of the receptor, which can inhibit melanomagenesis in mice.
- Shuyang Chen
- , Changpeng Han
- & Rutao Cui
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Article
| Open AccessKindlin-2 links mechano-environment to proline synthesis and tumor growth
The mechano-properties of the Extracellular Matrix (ECM) are important for tumorigenesis. Here, the authors show that the stiffening of the ECM promotes translocation of the focal adhesion protein—Kindlin-2—to the mitochondria, where it interacts with the proline synthesis enzyme PYCR1, stimulating proline synthesis and cell proliferation.
- Ling Guo
- , Chunhong Cui
- & Chuanyue Wu
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