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| 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 AccessMulti-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma
There has been a drastic increase in detection of lung nodules, many of which are precancers, preinvasive, minimally invasive or sometimes invasive lung cancers. Here, Hu et al. perform multi-region exome sequencing to discern the evolutional trajectory from precancers to invasive lung cancers.
- Xin Hu
- , Junya Fujimoto
- & Jianjun Zhang
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Article
| Open AccessSmall extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma
Cancer cells employ a variety of ways to escape the immune system. Here, the authors show that ovarian cancer cells produce small extracellular vescicles containing arginase 1 that are taken up by dendritic cells in the draining lymph nodes, resulting in inhibition of antigen-specific T-cell proliferation.
- Malgorzata Czystowska-Kuzmicz
- , Anna Sosnowska
- & Jakub Golab
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Article
| Open AccessUpper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling
Upper tract urothelial carcinoma (UTUC) is an aggressive cancer and largely uncharacterised cancer. Here, Faltas and colleagues report its distinctive molecular and immune landscape compared to urothelial carcinoma of the bladder and explore the role of FGFR3 signaling in UTUC biology.
- Brian D. Robinson
- , Panagiotis J. Vlachostergios
- & Bishoy M. Faltas
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Article
| Open AccessUncovering the signaling landscape controlling breast cancer cell migration identifies novel metastasis driver genes
Triple-negative breast cancers (TNBC) have enhanced migratory behaviour. Here, the authors perform a phenotypic imaging-based RNAi screen to identify several genes associated with regulation of migratory phenotypes and show that one of the regulators, PRPF4B, mediates metastasis in TNBC in mice.
- Esmee Koedoot
- , Michiel Fokkelman
- & Bob van de Water
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Article
| Open AccessMulti-immersion open-top light-sheet microscope for high-throughput imaging of cleared tissues
Light-sheet microscopes are increasingly used for imaging cleared tissues, but have imposed constraints on sample geometries and protocols. Here the authors present a multi-immersion open-top light-sheet microscope to overcome these limitations and enable high-throughput imaging of samples processed with various clearing protocols.
- Adam K. Glaser
- , Nicholas P. Reder
- & Jonathan T. C. Liu
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Article
| Open AccessPoly(ADP-ribose) polymerase-1 antagonizes DNA resection at double-strand breaks
Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates local chromatin relaxation and the recruitment of DNA repair factors at double strand breaks site (DSBs). Here the authors reveal that PARP-1 acts as a critical regulator of DNA end resection of DSBs.
- Marie-Christine Caron
- , Ajit K. Sharma
- & Jean-Yves Masson
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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 AccessMyc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma
PARP inhibitors are mainly used to treat BRCA1/2 mutated cancers. Here, the authors show that MYC amplified glioblastomas are sensitive to PARP inhibition due to CDK18 repression, which impairs ATR regulated homologous recombination repair, and that ATR inhibition sensitises glioblastomas to PARP inhibition.
- Jian-Fang Ning
- , Monica Stanciu
- & Samuel D. Rabkin
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Article
| Open AccessSynthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia
Studies with patient derived xenografts are hampered by factors such as genetic variability and sample availability. Here, the authors generate a leukemia mouse model by lentiviral transduction of normal human cord blood and show an oncogenic role of HOXB genes.
- Manabu Kusakabe
- , Ann Chong Sun
- & Andrew P. Weng
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Article
| Open AccessFas signaling-mediated TH9 cell differentiation favors bowel inflammation and antitumor functions
Fas signalling induces apoptosis of activated T cells to maintain immune homeostasis. Here the authors show that Fas also induces PKC-β activation to promote NF-κB-mediated TH9 cell differentiation, while p38 activation by PKC-β antagonizes this effect, thereby supporting a synergy between p38 inhibitor and Fas for TH9 differentiation.
- Yingying Shen
- , Zhengbo Song
- & Jianli Wang
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Article
| Open AccessThe deubiquitylase OTUD3 stabilizes GRP78 and promotes lung tumorigenesis
The deubiquitylase OTUD3 can function as a tumour-suppressor by stabilizing PTEN. Here, the authors show that OTUD3 also has an oncogenic role in lung cancer by stabilizing the glucose-regulated protein GRP78.
- Tongde Du
- , Hongchang Li
- & Lingqiang Zhang
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Article
| Open AccessAn ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis
Polycomb Repressor Complex 2 (PRC2) is frequently up-regulated in cancers. Here, the authors show that the tyrosine kinase c-Src stimulates mitochondrial function to signal energy sufficiency to mTORC1, increasing translation of the PRC2 subunits EZH2 and SUZ12 to support ErbB2-dependent tumours.
- Harvey W. Smith
- , Alison Hirukawa
- & William J. Muller
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Article
| Open AccessTSPAN8 promotes cancer cell stemness via activation of sonic Hedgehog signaling
Tetraspanin 8 (TSPAN8) has been implicated in a number of different tumours, but the underlying mechanisms remain unclear. Here, in breast cancer the authors highlight a role for TSPAN8 in promoting tumorigenesis through the activation of Hedgehog signalling.
- Rongxuan Zhu
- , Olivier Gires
- & Hongxia Wang
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Article
| Open AccessA high-throughput screening and computation platform for identifying synthetic promoters with enhanced cell-state specificity (SPECS)
Synthetic promoters can be superior to native ones but the design is challenging without knowledge of gene regulation. Here the authors develop a pipeline that allows for screening a synthetic promoter library to identify high performance promoters in potentially any given cell state of interest.
- Ming-Ru Wu
- , Lior Nissim
- & Timothy K. Lu
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Article
| Open AccessMutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness
The role of histone mutations in leukemogenesis remains largely unexplored. In this study of AML, the authors show that histone mutations are early events that drive a more aggressive phenotype.
- Meaghan Boileau
- , Margret Shirinian
- & Kolja Eppert
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Article
| Open AccessDeath effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer
The use of of CDK4/6 inhibitors to treat patients with TNBC is limited by loss of Rb. Here, the authors show that a combination of CDK4/6 inhibitor and EGFR inhibitor is effective against DEDD-overexpressing TNBC, independent of Rb status.
- Yingjia Ni
- , Keon R. Schmidt
- & Siyuan Zhang
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Article
| Open AccessABCB1 protects bat cells from DNA damage induced by genotoxic compounds
Bats possess an extended lifespan compared to most mammals of their size, and have a low cancer incidence. Here the authors show that several bat species exhibit resistance to genotoxic agents that is in part attributable to high expression of the ABCB1 transporter.
- Javier Koh
- , Yoko Itahana
- & Koji Itahana
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Article
| Open AccessLong-read sequencing unveils IGH-DUX4 translocation into the silenced IGH allele in B-cell acute lymphoblastic leukemia
The IGH@ proto-oncogene translocation is a known genomic driver in several blood cancers. Here, the authors show that IGH-DUX4 translocation occurs on the silenced IGH allele avoiding toxic high-level expression of DUX4 in B-ALL.
- Liqing Tian
- , Ying Shao
- & Jinghui Zhang
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Article
| Open Accessm6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade
FTO is an m6A demethylase. Here, the authors show that FTO promotes melanoma tumorigenicity and contributes to resistance to anti-PD1 blockade, while FTO inhibition sensitizes melanoma to anti-PD1 blockade.
- Seungwon Yang
- , Jiangbo Wei
- & Yu-Ying He
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Article
| Open AccessIntegrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer
Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) come with a dismal prognosis. Here, Yoo and colleagues reveal the genomic and transcriptomic landscape of ATC and DTC, highlighting potential therapeutic vulnerabilities.
- Seong-Keun Yoo
- , Young Shin Song
- & Jeong-Sun Seo
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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 AccessIntegrative inference of subclonal tumour evolution from single-cell and bulk sequencing data
Intra-tumour heterogeneity provides important information about subclonal tumour evolution. Here, the authors develop B-SCITE, a computational method for inferring tumour phylogenies from combined single-cell and bulk sequencing data.
- Salem Malikic
- , Katharina Jahn
- & Niko Beerenwinkel
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Article
| Open AccessMetabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation
Cancer cells must develop distinct metabolic adaptations to survive in challenging metastatic environments. Here, the authors find, via an in vivo RNAi screen, that the aldo-keto reductase AKR1B10 limits the toxic side effects of oxidative stress to sustain fatty acid oxidation and promote metastatic colonisation.
- Antoinette van Weverwijk
- , Nikolaos Koundouros
- & Clare M. Isacke
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Article
| Open AccessProbabilistic controllability approach to metabolic fluxes in normal and cancer tissues
Metabolic rewiring is a feature of many cancers. Here, the authors combine control theory and flux correlation analysis to study the transition of healthy metabolic networks to cancer states, and find that cancer metabolism is characterized by more streamlined flux distributions.
- Jean-Marc Schwartz
- , Hiroaki Otokuni
- & Jose C. Nacher
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Article
| Open AccessIdentification of metabolic vulnerabilities of receptor tyrosine kinases-driven cancer
Cancer subtypes may have distinct metabolic vulnerabilities that can be exploited for therapeutic interventions. Here, the authors show that in lung cancer, genetic activation of distinct oncogenic receptor tyrosine kinases results in unique metabolic liabilities and, in particular, EGFR aberrant cancers rely on the serine biosynthetic pathway while FGFR aberrant cancers rely on glycolysis.
- Nan Jin
- , Aiwei Bi
- & Min Huang
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Article
| Open AccessRegulating intracellular fate of siRNA by endoplasmic reticulum membrane-decorated hybrid nanoplexes
The silencing efficiency of siRNA delivered by non-viral cationic vectors is limited due to endosomal/lysosomal degradation. Here, the authors develop endoplasmic reticulum-coated vesicles as a biomimetic vector for siRNA delivery and show that they improve inhibition of tumor growth in mice in vivo.
- Chong Qiu
- , Hu-Hu Han
- & Qiang Zhang
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Article
| Open AccessFOXF2 reprograms breast cancer cells into bone metastasis seeds
Bone metastasis in breast cancer patients causes major skeletal-related complications. Here, the authors show that FOXF2/BMP/SMAD pathway plays a major role in bone metastasis and suggest targeting this axis to manage bone metastasis.
- Shuo Wang
- , Gui-Xi Li
- & Yu-Mei Feng
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Article
| Open AccessTargeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia
There is increasing evidence that epigenetic mechanisms contribute to therapeutic resistance in cancer. Here the authors study AML patient samples and a mouse model of non-genetic resistance and find that transcriptional plasticity drives stable epigenetic resistance, and identify regulators of enhancer function as important modulators of resistance.
- Charles C. Bell
- , Katie A. Fennell
- & Mark A. Dawson
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Article
| Open AccessAdenoviral vaccine targeting multiple neoantigens as strategy to eradicate large tumors combined with checkpoint blockade
Vaccination against neo-antigens has resulted in an effective antitumor response in several models. Here, the authors show that delivery of larger sets of neo-antigens using an adenovirus-based vaccination platform, results in much better tumor protection when combined with checkpoint blockade in a mouse model of advanced disease.
- Anna Morena D’Alise
- , Guido Leoni
- & Elisa Scarselli
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Article
| Open AccessSmall-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia
The RNA binding protein MUSASHI-2 (MSI2) is a potential therapeutic target for acute myeloid leukemia. Here the authors identify a small molecule inhibitor of MSI2 and characterize its effects in a murine leukemia model.
- Gerard Minuesa
- , Steven K. Albanese
- & Michael G. Kharas
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Article
| Open AccessRegulation of CAR T cell-mediated cytokine release syndrome-like toxicity using low molecular weight adapters
Chimeric antigen receptor (CAR) T cell anti-cancer therapies might result in toxic side effects. Here the authors present a strategy based on the modulation of CAR T cells via administration of a bispecific adapter that target them to cancer cells, resulting in diminished CAR-T cells toxicity and enhanced solid tumor eradication.
- Yong Gu Lee
- , Haiyan Chu
- & Philip S. Low
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Article
| Open AccessRan promotes membrane targeting and stabilization of RhoA to orchestrate ovarian cancer cell invasion
Ran, a nucleus-cytoplasm shuttle protein, is implicated in cancer development and survival. Here, the authors show that Ran binds RhoA to impair its degradation and allow its localisation to the plasma membrane of ovarian cancer cells for tumour invasion.
- Kossay Zaoui
- , Zied Boudhraa
- & Anne-Marie Mes-Masson
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Article
| Open AccessCommunity assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.
- Michael P. Menden
- , Dennis Wang
- & Julio Saez-Rodriguez
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Article
| Open AccessNon-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion
Cancer cells develop specific metabolic adaptations. Here, the authors show that in prostate cancer models, the ubiquitin ligase Hect9 promotes tumor growth by accelerating glucose metabolism via ubiquitination of Hexokinase 2, a central regulator of glycolysis.
- Hong-Jen Lee
- , Chien-Feng Li
- & Chia-Hsin Chan
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Article
| Open AccessKRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe
Mutant RAS family members occur in a wide range of tumour types, and there is a great interest in identifying isoform-specific inhibitors. Here, the authors characterise two designed ankyrin repeat proteins (DARPins) that specifically inhibit the KRAS isoform by binding to the region around the KRAS-specific residue histidine 95 and show that they affect KRAS/effector interactions in different ways.
- Nicolas Bery
- , Sandrine Legg
- & Terence H. Rabbitts
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Article
| Open AccessLncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling
The induction of neuroendocrine differentiation occurs in enzalutamide treated castration resistant prostate cancer. Here, the authors show that lncRNA-21 mediates enzalutamide induced neuroendocrine differentiation through EZH2/STAT axis and EZH2 inhibition suppresses this differentiation.
- Jie Luo
- , Keliang Wang
- & Chawnshang Chang
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Article
| Open AccessA pan-cancer analysis of synonymous mutations
Synonymous mutations do not alter amino acid sequence but may exert oncogenic effects in other ways. Here, the authors present a catalogue of synonymous mutations in cancer and characterise their properties.
- Yogita Sharma
- , Milad Miladi
- & Sven Diederichs
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Article
| Open AccessExploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence
Senescence induction is known to induce stable proliferation arrest. Here, the authors show that sustained PARP inhibition promotes a reversible p53-independent senescence, and that PARP inhibition is synthetic lethal when combined with senolytic agents in pre-clinical models of ovarian and breast cancer.
- Hubert Fleury
- , Nicolas Malaquin
- & Francis Rodier
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Article
| Open AccessLIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy
LIF is a pleiotropic cytokine that promotes an immunosuppressive microenvironment and has critical functions in embryonic development. Here, the authors show that LIF regulates CD8+ T cell tumor infiltration in cancer by repressing CXCL19 and promoting the presence of protumoral macrophages and thatLIF inhibition, via neutralizing antibodies, promotes T cell infiltration and synergizes with immune checkpoint inhbitors resulting in tumor regression and immunological memory.
- Mónica Pascual-García
- , Ester Bonfill-Teixidor
- & Joan Seoane
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Article
| Open AccessTumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma
Astrocytes play important roles in neuroinflammatory diseases. Here the authors characterize human glioblastoma-associated astrocytes by gene expression and demonstrate their immunosuppressive role promoted by interactions with tumor and microglia cells in an organotypic model.
- Dieter Henrik Heiland
- , Vidhya M. Ravi
- & Oliver Schnell
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Article
| Open AccessTranslatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells
The ribosomal protein RPL10 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). Here, the authors show that it promotes proliferation of T-ALL cells by upregulating the serine biosynthesis enzyme phosphoserine phosphatase which in turn modulates serine and glycine metabolism.
- Kim R. Kampen
- , Laura Fancello
- & Kim De Keersmaecker
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Article
| Open AccessSHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers
Targeted inhibition of the ERK-MAPK pathway is challenged by the development of resistance and toxicity. Here, the authors show that SHOC2 genetic inhibition impairs lung tumour development and improves MEK inhibitor efficacy in RAS- and EGFR-mutant cells.
- Greg G. Jones
- , Isabel Boned del Río
- & Pablo Rodriguez-Viciana
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Article
| Open AccessCordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents
Radiation damage causes DNA foci to form and senescence, causing ulcers. Here, the authors show that a naturally occurring adenosine analogue, cordycepin, prevents cell senescence via an increase in AMPK/NRF2, so blocking ulcers caused by radiation on skin/intestine/tongue damage in rodents.
- Ziwen Wang
- , Zelin Chen
- & Chunmeng Shi
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Article
| Open AccessCHML promotes liver cancer metastasis by facilitating Rab14 recycle
Metastasis-associated recurrence is a major cause of poor prognosis in hepatocellular carcinoma. Here, the authors show that expression of choroideremia-like (CHML) is elevated and associates with poor prognosis in hepatocellular carcinoma, and mechanistically CHML promotes metastasis in a Rab14-dependent manner.
- Tian-Wei Chen
- , Fen-Fen Yin
- & Dong Xie
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Article
| Open AccessAPC/CCDH1 synchronizes ribose-5-phosphate levels and DNA synthesis to cell cycle progression
Ribose-5-phosphate (R5P) is required for DNA synthesis, but how this is regulated during cell cycle progression is unclear. Here the authors report that the cell cycle regulator APC/C-CDH1 synchronizes cell cycle progression with R5P-derived DNA synthesis by controlling TKTL1 stability
- Yang Li
- , Cui-Fang Yao
- & Jian-Yuan Zhao
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Article
| Open AccessStructural and functional consequences of the STAT5BN642H driver mutation
Hyper-activated STAT5B and its disease-causing variants are of interest as cancer drug targets. Here the authors combine cell based studies, X-ray crystallography, biophysical experiments and MD simulations to structurally and functionally characterize the STAT5BN642H mutant found in aggressive T-cell leukemia and lymphomas and find that it has an increased affinity for self-dimerization.
- Elvin D. de Araujo
- , Fettah Erdogan
- & Patrick T. Gunning
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Article
| Open AccessPRL3-zumab as an immunotherapy to inhibit tumors expressing PRL3 oncoprotein
Phosphatase of regenerating liver 3 (PRL3) is usually found intracellularly, and is over-expressed in cancer cells. Here the authors show that PRL-3 is also detectable on cell surface, and can be recognized by PRL3-zumab to recruit immune cells into tumor to promote anti-tumor immunity, thereby implicating PRL-3 as a potential tumor antigen.
- Min Thura
- , Abdul Qader Al-Aidaroos
- & Qi Zeng
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Article
| Open AccessCaMKK2 in myeloid cells is a key regulator of the immune-suppressive microenvironment in breast cancer
Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) is highly expressed in several cancers. Here the authors investigate the role of CaMKK2 expression in the tumour microenvironment and show that CaMKK2 expression in tumour-associated macrophages promotes tumour growth by suppressing T cell anti-tumour activity.
- Luigi Racioppi
- , Erik R. Nelson
- & Donald P. McDonnell
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